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Simple Summary: Recent advancements in cancer research have proven immunotherapies to be a promising strategy for the treatment of hematological malignancies. The bispecific antibody (BsAb) format was developed to overcome the issues of monoclonal antibody-based therapies. T-cell engagers (TCEs) are BsAbs, which directly activate T-cells and their anti-tumor features, ultimately resulting in the lysis of the targeted tumor cells. In 2014, the FDA approved blinatumomab for treatment of acute lymphoblastic leukemia. As of November 2023, seven clinically approved TCE therapies are on the market. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects. [ABSTRACT FROM AUTHOR]

Simple Summary: This article addresses the topic of primary immunodeficiencies, with particular emphasis on antibody deficiencies with near-normal immunoglobulin levels or hyperimmunoglobulinemia. This paper goes beyond genetics and emphasizes the importance of the immune system and particularly immune checkpoints and Epstein–Barr virus (EBV) reactivation in the context of these disorders. The article delves into the immune dysregulations occurring in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical picture of patients and, in the future, may contribute to the development of cancer, especially those related to hematological malignancies. Disturbances observed in the immunopathogenesis of the presented diseases go beyond the accepted scheme, with the development of PID largely associated only with genetic disorders, and the article emphasizes that the regulation of immunity and virus reactivation also contributes to the progression of PID. This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein–Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies. [ABSTRACT FROM AUTHOR]

Mutations and the glycosylation of epitopes can convert immunogenic epitopes into non-immunogenic ones via natural selection or evolutionary pressure, thereby decreasing their sensitivity to neutralizing antibodies. Based on Thomas Francis's theory, memory B and T cells induced during primary infections or vaccination will freeze the new mutated epitopes specific to naïve B and T cells from the repertoire. On this basis, some researchers argue that the current vaccines derived from the previous strains of the SARS-CoV-2 virus do not increase immunity and may also prevent the immune response against new epitopes. However, evidence shows that even if the binding affinity is reduced, the previous antibodies or T cell receptors (TCRs) can still bind to this new epitope of the Beta, Gamma, and Delta variant if their concentration is high enough (from a booster injection) and neutralize the virus. This paper presents some convincing immunological reasons that may challenge this theory and argue for the continuation of universal vaccination to prevent further mutations of the SARS-CoV-2 virus. Simultaneously, the information presented can be used to develop vaccines that target novel epitopes or create new recombinant drugs that do not lose their effectiveness when the virus mutates. [ABSTRACT FROM AUTHOR]

The cells of acute myeloid leukemia are defined by clonal growth and heterogenous immunophenotypes. Chimeric antigen receptors (CARs) commonly recognize molecular targets by single-chain antibody fragments (scFvs) specific to a tumor-associated antigen. However, ScFvs may form aggregates, thus stimulating tonic CAR T-cell activation and reducing CAR T-cell functioning in vivo. Harnessing natural ligands as recognition parts of CARs, specific targeting of membrane receptors can be achieved. Previously, we presented ligand-based Flt3-CAR T-cells targeting the Flt3 receptor. The extracellular part of Flt3-CAR consisted of full-size Flt3Lg. Meanwhile, upon recognition, Flt3-CAR may potentially activate Flt3, triggering proliferative signaling in blast cells. Moreover, the long-lasting presence of Flt3Lg may lead to Flt3 downregulation. In this paper, we present mutated Flt3Lg-based Flt3m-CAR ('m'—for 'mutant') T-cells targeting Flt3. The extracellular part of Flt3m-CAR consists of full-length Flt3Lg-L27P. We have determined that ED50 for recombinant Flt3Lg-L27P produced in CHO cells is at least 10-fold higher than for the wild-type Flt3Lg. We show that the mutation in the recognizing domain of Flt3m-CAR did not affect the specificity of Flt3m-CAR T-cells when compared to Flt3-CAR T-cells. Flt3m-CAR T-cells combine the specificity of ligand–receptor recognition with reduced Flt3Lg-L27P bioactivity, leading to potentially safer immunotherapy. [ABSTRACT FROM AUTHOR]

New short-lived strains of mice (SAM-P), which have been developed by Takeda et al. (1981), show a defective antibody response to T dependent (TD) antigen in vitro, as demonstrated in the accompanying paper (see page 419). In the present study, we investigated the cellular site of the defect, using a cell culture system. In this paper, it is demonstrated that T-helper (Th) cell activity for the antibody response to TD antigen is impaired, while other cellular immune responses, e.g. mixed leucocyte reaction, cytotoxic T-lymphocyte response, and delayed-type hypersensitivity reaction, are normal. These results suggest that the defect in T-helper subset is limited in helper function for the antibody response, and that the helper function for the cell-mediated immune responses is intact. These two functions of the T-helper subset are apparently regulated in a different manner. The SAM-P strains of mice may thus serve as an appropriate model for studying functional heterogeneity in T-helper/inducer cell subsets. [ABSTRACT FROM AUTHOR]

Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A® and Alhydrogel® as adjuvants to further stimulate the immune response. MPL-A® induces a Th1-mediated immune response and Alhydrogel® (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of −19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4+ helper and CD8+ cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally. [ABSTRACT FROM AUTHOR]

V-set immunoglobulin domain-containing 4 (VSIG4) is a B7 family protein with known roles as a C3 fragment complement receptor involved in pathogen clearance and a negative regulator of T cell activation by an undetermined mechanism. VSIG4 expression is specific for tumor-associated and select tissue-resident macrophages. Increased expression of VSIG4 has been associated with worse survival in multiple cancer indications. Based upon computational analysis of transcript data across thousands of tumor and normal tissue samples, we hypothesized that VSIG4 has an important role in promoting M2-like immune suppressive macrophages and that targeting VSIG4 could relieve VSIG4-mediated macrophage suppression by repolarizing tumor-associated macrophages (TAMs) to an inflammatory phenotype. We have also observed a cancer-specific pattern of VSIG4 isoform distribution, implying a change in the functional regulation in cancer. Through a series of in vitro, in vivo, and ex vivo assays we demonstrate that anti-VSIG4 antibodies repolarize M2 macrophages and induce an immune response culminating in T cell activation. Anti-VSIG4 antibodies induce pro-inflammatory cytokines in M-CSF plus IL-10-driven human monocyte-derived M2c macrophages. Across patient-derived tumor samples from multiple tumor types, anti-VSIG4 treatment resulted in the upregulation of cytokines associated with TAM repolarization and T cell activation and chemokines involved in immune cell recruitment. VSIG4 blockade is also efficacious in a syngeneic mouse model as monotherapy as it enhances efficacy in combination with anti-PD-1, and the effect is dependent on the systemic availability of CD8+ T cells. Thus, VSIG4 represents a promising new target capable of triggering an anti-cancer response via multiple key immune mechanisms. [ABSTRACT FROM AUTHOR]

In this paper we propose and analyze a pathogen dynamics model with antibody and Cytotoxic T Lymphocyte (CTL) immune responses. We incorporate latently infected cells and three distributed time delays into the model. We show that the solutions of the proposed model are nonnegative and ultimately bounded. We derive four threshold parameters which fully determine the existence and stability of the five steady states of the model. Using Lyapunov functionals, we established the global stability of the steady states of the model. The theoretical results are confirmed by numerical simulations. [ABSTRACT FROM AUTHOR]

In this paper, we report the development of a label-free biosensor, based on surface plasmon resonance, for real-time monitoring of captured human CD4+T-cells, and their dynamic cytokine production upon specific antigen stimulation. Microarrays of CD4+T-cells, and interferon gamma (IFN-γ) specific antibody (Ab) spots were printed side by side onto the poly(OEGMA-co-HEMA) matrix. The placement of CD4+ T-cells near the anti IFN-γ Ab-coated spots ensured a high local concentration of secreted IFN-γ for detection. We have demonstrated that this approach enables the detection of tuberculosis (TB) infection in clinical samples, with an overall sensitivity of 85.5% and an overall specificity of 97.7%. [ABSTRACT FROM AUTHOR]

Before the emergence of SARS-CoV-1, MERS-CoV, and most recently, SARS-CoV-2, four other coronaviruses (the alpha coronaviruses NL63 and 229E and the beta coronaviruses OC43 and HKU1) had already been circulating in the human population. These circulating coronaviruses all cause mild respiratory illness during the winter seasons, and most people are already infected in early life. Could antibodies and/or T cells, especially against the beta coronaviruses, have offered some form of protection against (severe) COVID-19 caused by infection with SARS-CoV-2? Related is the question of whether survivors of SARS-CoV-1 or MERS-CoV would be relatively protected against SARS-CoV-2. More importantly, would humoral and cellular immunological memory generated during the SARS-CoV-2 pandemic, either by infection or vaccination, offer protection against future coronaviruses? Or rather than protection, could antibody-dependent enhancement have taken place, a mechanism by which circulating corona antibodies enhance the severity of COVID-19? Another related phenomenon, the original antigenic sin, would also predict that the effectiveness of the immune response to future coronaviruses would be impaired because of the reactivation of memory against irrelevant epitopes. The currently available evidence indicates that latter scenarios are highly unlikely and that especially cytotoxic memory T cells directed against conserved epitopes of human coronaviruses could at least offer partial protection against future coronaviruses. [ABSTRACT FROM AUTHOR]

The clinical development of an effective Chlamydia vaccine requires in-depth understanding of how well protective pre-clinical immune signatures translate to humans. Here, we report a comparative immunological characterization of CTH522/CAF®01 in female mice and humans. We find a range of immune signatures that translate from mouse to human, including a Th1/Th17 cytokine profile and antibody functionality. We identify vaccine-induced T cell epitopes, conserved among Chlamydia serovars, and previously found in infected individuals. Using the mouse model, we show that the common immune signature protected against ascending infection in mice, and vaccine induced antibodies could delay bacterial ascension to the oviduct, as well as development of pathology, in a T cell depleted mouse model. Finally, we demonstrate long-lasting immunity and protection of mice one year after vaccination. Based on the results obtained in the present study, we propose to further investigate CTH522/CAF®01 in a phase IIb study. Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate. [ABSTRACT FROM AUTHOR]

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female rabbits with monovalent (gB-1), bivalent (gB-1+gB-3), or pentavalent (gB-1+gB-2+gB-3+gB-4+gB-5) gB lipid nanoparticle-encapsulated nucleoside-modified RNA (mRNA–LNP) vaccines. The multivalent vaccine groups did not demonstrate a higher magnitude or breadth of the IgG response to the gB ectodomain or cell-associated gB compared to that of the monovalent vaccine. Also, the multivalent vaccines did not show an increase in the breadth of neutralization activity and antibody-dependent cellular phagocytosis against HCMV strains encoding distinct gB genotypes. Interestingly, peripheral blood mononuclear cell-derived gB-2-specific T-cell responses elicited by multivalent vaccines were of a higher magnitude compared to that of monovalent vaccinated animals against a vaccine-mismatched gB genotype at peak immunogenicity. Yet, no statistical differences were observed in T cell response against gB-3 and gB-5 variable regions among the three vaccine groups. Our data suggests that the inclusion of multivalent gB antigens is not an effective strategy to increase the breadth of anti-HCMV gB antibody and T cell responses. Understanding how to increase the HCMV vaccine protection breadth will be essential to improve the vaccine efficacy. [ABSTRACT FROM AUTHOR]

As described in an accompanying paper, trinitrophenyl (TNP) modification of pork insulin (PI) at the A1 glycine position allows this molecule to stimulate a proliferative response in H-2b (B10) mice. We now show that this antigen stimulates low IgG responses in the same strain of mice. Our results show that T-cell help and proliferation may therefore be regulated independently. [ABSTRACT FROM AUTHOR]

MRL-lpr mice and their congenic counterparts MRL- + spontaneously develop an autoimmune disease that resembles systemic lupus erythematosus in humans. The two strains, although congenic, differ by a considerable number of disease parameters, reflecting the expression of the lpr autosomal recessive gene. One paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigated a possible lpr gene-encoded macrophage defect in these mice. It was found, however, that both the MRL- + and MRL-lpr mice failed to divide in response to Con A, the lack of division correlating with an inability to secrete the growth promoter interleukin-2. In MRL- + mice and young MRL-lpr mice this non-responsiveness was corrected by the addition of normal CRA PEC. The defect could not be explained by a failure of M RL- + or M RL-lpr peritoneal exudate cells to quantitatively or qualitatively provide a source of interleukin-1 to Con A-activated T cells or by the possibility that the peritoneal exudate cells were blocked in their function by the presence of sera-derived autoantibodies and/or immune complexes on their membranes. We postulate that the inability of T cells to proliferate in MRL congenic mice can be explained by two defects: (i) the failure of antigen-presenting cells in MRL- + and MRL-lpr to provide the necessary signals to immunocompetent T cells, this defect not being associated with the lpr gene, and (ii) the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay system. [ABSTRACT FROM AUTHOR]

T-colony formation can be induced in PHA-stimulated peripheral blood mononuclear cells (PBM) from man, but not in PHA-stimulated purified T cells, the latter requiring the presence of factors produced by PHA-stimulated PBM and termed T-colony promoting activity (TCPA). In this paper, we demonstrate that interleukin-2 (IL-2), the growth hormone of T lymphocytes, controls T-colony formation. We show that: (i) IL-2 activity and TCPA produced by PHA-activated PBM are co-purified by gel filtration and chromatography on blue agarose, a procedure which yields a 850-fold IL-2 purification; (ii) recombinant IL-2, produced by genetically manipulated Eseherichia coli, can induce T-colony formation in PHA-stimulated purified T cells; (iii) Monoclonal antibody against the IL-2 receptor (anti-Tac antibody) completely inhibits the T-colony formation in PHA-stimulated PBM when directly added to the culture system. [ABSTRACT FROM AUTHOR]

The regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing “idiotypic network theory” and “Treg cell theory” into an “anti-idiotypic Treg cell theory.” Based on this hypothesis, an “active anti-idiotypic therapy” for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to selfantigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases. [ABSTRACT FROM AUTHOR]

The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards autologous T cell, vaccine, and antibody-based therapeutic modalities. Here, using complementary biophysical and computational methods, we characterize recurrent RAS55-64 Q61 neoepitopes presented by the common HLA-A*01:01 allotype. We integrate sparse NMR restraints with Rosetta docking to determine the solution structure of NRASQ61K/HLA-A*01:01, which enables modeling of other common RAS55-64 neoepitopes. Hydrogen/deuterium exchange mass spectrometry experiments alongside molecular dynamics simulations reveal differences in solvent accessibility and conformational plasticity across a panel of common Q61 neoepitopes that are relevant for recognition by immunoreceptors. Finally, we predict binding and provide structural models of NRASQ61K antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy. The authors use an integrative structural biology approach to elucidate molecular features of the RAS Q61 family of public tumor antigens. This information can be used to develop targeted therapeutics to combat a range of cancers. [ABSTRACT FROM AUTHOR]

Background: Classical swine fever and porcine reproductive and respiratory syndrome have seriously affected the development of the swine breeding industry in China. Vaccine immunization remains the main way to prevent these infections. The aim of this study was to establish an optimized protocol for vaccine immunization against classical swine fever virus (CSFV) and porcine reproductive and respiratory syndrome virus (PRRSV). Methods: Blood samples were collected from the anterior vena cava of pigs after immunization, and blood indices, secreted levels of specific antibodies and neutralizing antibodies associated with humoral immunity, the proliferation capacity of T lymphocytes as a measure of cellular immunity, and secreted levels of IFN-γ and TNF-α were determined. Results: The results showed that simultaneous immunization against CSFV and PRRSV infections induced strong and specific humoral and T-cellular immune responses, high levels of cytokine IFN-γ secretion and delayed secretion of cytokine TNF-α. Moreover, significantly higher lymphocyte percentages and red blood cell and leukocyte counts were found in the group simultaneously immunized against CSFV and PRRSV. However, no statistically significant differences were observed in hemoglobin values, neutrophil counts, and median cell percentages among the S + PRRS, PRRS-S, and S-PRRS groups. Conclusion: This study demonstrated that simultaneous immunization against CSFV and PRRSV had the advantages of inducing a rapid, enhanced, and long-lasting immune response. These findings provide a theoretical basis for the establishment of a reasonable and optimized vaccine immunization protocol against CSFV and PRRSV in combination with a variety of other vaccine inoculations. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes a high disease burden in older adults. An effective vaccine for this RSV-primed population may need to boost/elicit robust RSV-neutralizing antibody responses and recall/induce RSV-specific T cell responses. To inform the selection of the vaccine formulation for older adults, RSVPreF3 (RSV fusion glycoprotein engineered to maintain the prefusion conformation) with/without AS01 adjuvant was evaluated in mice and bovine RSV infection-primed cattle. In mice, RSVPreF3/AS01 elicited robust RSV-A/B-specific neutralization titers and RSV F-specific polyfunctional CD4+ T cell responses exceeding those induced by non-adjuvanted RSVPreF3. In primed bovines, RSVPreF3/AS01 tended to induce higher pre-/post-vaccination fold-increases in RSV-A/B-specific neutralization titers relative to non-adjuvanted and Alum-adjuvanted RSVPreF3 formulations, and elicited higher RSV F-specific CD4+ T cell frequencies relative to the non-adjuvanted vaccine. Though AS01 adjuvanticity varied by animal species and priming status, RSVPreF3/AS01 elicited/boosted RSV-A/B-specific neutralization titers and RSV F-specific CD4+ T cell responses in both animal models, which supported its further clinical evaluation as prophylactic candidate vaccine for older adults. [ABSTRACT FROM AUTHOR]

HIV affects more than 38 million people worldwide. Although HIV can be effectively treated by lifelong combination antiretroviral therapy, only a handful of patients have been cured. Therapeutic vaccines that induce robust de novo immune responses targeting HIV proteins and latent reservoirs will likely be integral for functional HIV cure. Our study shows that immunization of naïve rhesus macaques with arenavirus-derived vaccine vectors encoding simian immunodeficiency virus (SIVSME543 Gag, Env, and Pol) immunogens is safe, immunogenic, and efficacious. Immunization induced robust SIV-specific CD8+ and CD4+ T-cell responses with expanded cellular breadth, polyfunctionality, and Env-binding antibodies with antibody-dependent cellular cytotoxicity. Vaccinated animals had significant reductions in median SIV viral load (1.45-log10 copies/mL) after SIVMAC251 challenge compared with placebo. Peak viral control correlated with the breadth of Gag-specific T cells and tier 1 neutralizing antibodies. These results support clinical investigation of arenavirus-based vectors as a central component of therapeutic vaccination for HIV cure. [ABSTRACT FROM AUTHOR]

Accurate structural information plays a crucial role in comprehending biological processes and designing drugs. Indeed, the remarkable precision of the AlphaFold2 has facilitated significant advancements in predicting molecular structures, encompassing antibodies and antigens. This breakthrough has paved the way for rational drug design, ushering in new possibilities in the field of pharmaceutical development. Within this study, performing analysis and humanization guided by the structures predicted by AlphaFold2. Notably, the resulting humanized antibody, h3D5-hIgG1, demonstrated exceptional binding affinity to the PD-L1 protein. The KD value of parental antibody 3D5-hIgG1 was increased by nearly 7 times after humanization. Both h3D5-hIgG1 and 3D5-hIgG1 bound to cells expressing human PD-L1 with EC50 values of 5.13 and 9.92nM, respectively. Humanization resulted in a twofold increase in the binding capacity of the antibody, with h3D5-hIgG1 exhibiting superior performance compared to the parental antibody 3D5-hIgG1. Furthermore, h3D5-hIgG1 promoted cytokine secretion of T cells, and significantly suppressed MC38-hPD-L1 tumor growth. This study highlights the potential for artificial intelligence-assisted drug development, which is poised to become a prominent trend in the future. [ABSTRACT FROM AUTHOR]

Enhancement or inhibition of cytokine signaling and corresponding immune cells responses are critical factors in various disease treatments. Cytokine signaling may be inhibited by cytokine-neutralizing antibodies (CNAs), which prevents further activation of cytokine receptors. However, CNAs may result in enhanced—instead of inhibitory—cytokine signaling (an “agonistic effect”) in various in vitro and in vivo experiments. This may lead to lack of efficacy or adverse events for cytokine-inhibiting based medicines. Alternatively, cytokine-antibody complexes may produce stronger signaling vs. cytokine alone, thereby increasing the efficacy of stimulating cytokine-based drugs, at equal or lower cytokine doses. In this paper, the effect of cytokine signaling enhancement by a CNA was studied in a generic mathematical model of interleukin-4 (IL-4) driven T-cell proliferation. The occurrence of the agonistic effect depends upon the antibody-to-cytokine binding affinity and initial concentrations of antibody and cytokine. Model predictions were in agreement with experimental studies. When the cytokine receptor consists of multiple subunits with substantially differing affinities (e.g., IL-4 case), the choice of the receptor chain to be blocked by the antibody is critical, for the agonistic effect to appear. We propose a generic mechanism for the effect: initially, binding of the CNA to the cytokine reduces free cytokine concentration; yet, cytokine molecules bound within the cytokine-CNA complex—and released later and over time—are “rescued” from earlier clearance via cellular internalization. Hence, although free cytokine-dependent signalling may be less potent initially, it will also be more sustained over time; and given non-linear dynamics, it will lead ultimately to larger cellular effector responses, vs. the same amount of free cytokine in the absence of CNA. We suggest that the proposed mechanism is a generic property of {cytokine, CNA, receptor} triads, both in vitro and in vivo, and can occur in a predictable fashion for a variety of cytokines of the immune system. [ABSTRACT FROM AUTHOR]

This is a perspective based on the paper "Cloning of complementary DNA encoding T cell-replacing factor and identity with B cell growth factor II," by Kinashi et al. (1). We have been interested in understanding the molecular basis ofT-B cell cooperation for antibody formation. Although many investigators had described a number of different soluble factors that appeared to have biological relevance to T-B cell interactions, molecular basis of such active substances remained unknown for a long period of time. In this perspective, I will briefly summarize the history of the initial discovery of T cell-replacing factor/B cell growth factor II that appeared to be involved in B cell growth and differentiation, and outline the discovery and characterization of interleukin-5. Studies of interleukin-5 have provided strong evidence that a single cytokine exerts a variety of activities on diverse target cells. [ABSTRACT FROM AUTHOR]

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314). Authors utilise a cohort of healthcare workers, infected during the first wave of the SARS-CoV-2 pandemic, to assess symptom persistence and humoral and cellular immunity. [ABSTRACT FROM AUTHOR]

The intestinal epithelial receptor Guanylyl Cyclase C (GUCY2C) is a tumor-associated cell surface antigen expressed across gastrointestinal malignancies that can serve as an efficacious target for colorectal cancer immunotherapy. Here, we describe a yeast surface-display approach combined with an orthogonal peptide-based mapping strategy to identify the GUCY2C binding epitope of a novel anti-GUCY2CxCD3 bispecific antibody (BsAb) that recently advanced into the clinic for the treatment of cancer. The target epitope was localized to the N-terminal helix H2 of human GUCY2C, which enabled the determination of the crystal structure of the minimal GUCY2C epitope in complex with the anti-GUCY2C antibody domain. To understand if this minimal epitope covers the entire antibody binding region and to investigate the impact of epitope position on the antibody's activity, we further determined the structure of this interaction in the context of the full-length extracellular domain (ECD) of GUCY2C. We found that this epitope is positioned on the protruding membrane-distal helical region of GUCY2C and that its specific location on the surface of GUCY2C dictates the close spatial proximity of the two antigen arms in a diabody arrangement essential to the tumor killing activity of GUCY2CxCD3 BsAb. [ABSTRACT FROM AUTHOR]

One of the most preferable characteristics for a COVID-19 vaccine candidate is the ability to reduce transmission and infection of SARS-CoV-2, in addition to disease prevention. Unlike intramuscular vaccines, intranasal COVID-19 vaccines may offer this by generating mucosal immunity. In this open-label, randomised, multicentre, phase 3 clinical trial (CTRI/2022/02/40065; ClinicalTrials.gov: NCT05522335), healthy adults were randomised to receive two doses, 28 days apart, of either intranasal adenoviral vectored SARS-CoV-2 vaccine (BBV154) or licensed intramuscular vaccine, Covaxin®. Between April 16 and June 4, 2022, we enrolled 3160 subjects of whom, 2971 received 2 doses of BBV154 and 161 received Covaxin. On Day 42, 14 days after the second dose, BBV154 induced significant serum neutralization antibody titers against the ancestral (Wuhan) virus, which met the pre-defined superiority criterion for BBV154 over Covaxin®. Further, both vaccines showed cross protection against Omicron BA.5 variant. Salivary IgA titers were found to be higher in BBV154. In addition, extensive evaluation of T cell immunity revealed comparable responses in both cohorts due to prior infection. However, BBV154 showed significantly more ancestral specific IgA-secreting plasmablasts, post vaccination, whereas Covaxin recipients showed significant Omicron specific IgA-secreting plasmablasts only at day 42. Both vaccines were well tolerated. Overall reported solicited reactions were 6.9% and 25.5% and unsolicited reactions were 1.2% and 3.1% in BBV154 and Covaxin® participants respectively. [ABSTRACT FROM AUTHOR]

Background: Infections with Plasmodium ovale are widely distributed but rarely investigated, and the resulting burden of disease has been underestimated. Plasmodium ovale curtisi Duffy binding protein domain region II (PocDBP-RII) is an essential ligand for reticulocyte recognition and host cell invasion by P. ovale curtisi. However, the genomic variation, antigenicity and immunogenicity of PocDBP-RII remain major knowledge gaps. Methods: A total of 93 P. ovale curtisi samples were collected from migrant workers who returned to China from 17 countries in Africa between 2012 and 2016. The genetic polymorphism, natural selection and copy number variation (CNV) were investigated by sequencing and real-time PCR. The antigenicity and immunogenicity of the recombinant PocDBP-RII (rPocDBP-RII) protein were further examined, and the humoral and cellular responses of immunized mice were assessed using protein microarrays and flow cytometry. Results: Efficiently expressed and purified rPocDBP-RII (39 kDa) was successfully used as an antigen for immunization in mice. The haplotype diversity (Hd) of PocDBP-RII gene was 0.105, and the nucleotide diversity index (π) was 0.00011. No increased copy number was found among the collected isolates of P. ovale curtisi. Furthermore, rPocDBP-RII induced persistent antigen-specific antibody production with a serum IgG antibody titer of 1: 16,000. IFN-γ-producing T cells, rather than IL-10-producing cells, were activated in response to the stimulation of rPocDBP-RII. Compared to PBS-immunized mice (negative control), there was a higher percentage of CD4+CD44highCD62L− T cells (effector memory T cells) and CD8+CD44highCD62L+ T cells (central memory T cells) in rPocDBP-RII‑immunized mice. Conclusions: PocDBP-RII sequences were highly conserved in clinical isolates of P. ovale curtisi. rPocDBP-RII protein could mediate protective blood-stage immunity through IFN-γ-producing CD4+ and CD8+ T cells and memory T cells, in addition to inducing specific antibodies. Our results suggested that rPocDBP-RII protein has potential as a vaccine candidate to provide assessment and guidance for malaria control and elimination activities. [ABSTRACT FROM AUTHOR]

Anti-CTLA-4 antibodies have successfully elicited durable tumor regression in the clinic; however, long-term benefit is limited to a subset of patients for select cancer indications. The incomplete understanding of their mechanism of action has hindered efforts at improvement, with conflicting hypotheses proposing either antagonism of the CTLA-4: B7 axis or Fc effector-mediated regulatory T cell (Treg) depletion governing efficacy. Here, we report the engineering of a nonantagonistic CTLA-4 binding domain (b1s1e2) that depletes intratumoral Tregs as an Fc fusion. Comparison of b1s1e2-Fc to 9d9, an antagonistic anti-CTLA-4 antibody, allowed for interrogation of the separate contributions of CTLA-4 antagonism and Treg depletion to efficacy. Despite equivalent levels of intratumoral Treg depletion, 9d9 achieved more long-term cures than b1s1e2-Fc in MC38 tumors, demonstrating that CTLA-4 antagonism provided additional survival benefit. Consistent with prior reports that CTLA-4 antagonism enhances priming, treatment with 9d9, but not b1s1e2-Fc, increased the percentage of activated T cells in the tumor-draining lymph node (tdLN). Treg depletion with either construct was restricted to the tumor due to insufficient surface CTLA-4 expression on Tregs in other compartments. Through intratumoral administration of diphtheria toxin in Foxp3-DTR mice, we show that depletion of both intratumoral and nodal Tregs provided even greater survival benefit than 9d9, consistent with Treg-driven restraint of priming in the tdLN. Our data demonstrate that anti-CTLA-4 therapies require both CTLA-4 antagonism and intratumoral Treg depletion for maximum efficacy--but that potential future therapies also capable of depleting nodal Tregs could show efficacy in the absence of CTLA-4 antagonism. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Strik et al and Strik, D'Heans papers. To view these articles visit https://doi.org/10.1111/apt.13994 and https://doi.org/10.1111/apt.14071. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Duvvuri et al. (2010) Highly conserved cross-reactive CD4+ T-cell HA-epitopes of seasonal and the 2009 pandemic influenza viruses. Influenza and Other Respiratory Viruses 4(5), 249–258. Background The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre-existing immune memory. The absence of cross-reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre-existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter-pandemic influenza A viruses. Results We sought to identify potential CD4+ T cell epitopes and predict the level of cross-reactivity of responding T cells. By performing large-scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T-cell cross-reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T-cell cross-reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation ( P < 0·05). Conclusions  Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T-cell assays for understanding the inter-pandemic variability in severity and for planning treatment methods for emerging influenza viruses. [ABSTRACT FROM AUTHOR]

Celiac disease is a permanent intolerance to the gliadin fraction of wheat gluten and to similar barley and rye proteins that occurs in genetically susceptible subjects. After ingestion, degraded gluten proteins reach the small intestine and trigger an inappropriate T cell-mediated immune response, which can result in intestinal mucosal inflammation and extraintestinal manifestations. To date, no pharmacological treatment is available to gluten-intolerant patients, and a strict, life-long gluten-free diet is the only safe and efficient treatment available. Inevitably, this may produce considerable psychological, emotional, and economic stress. Therefore, the scientific community is very interested in establishing alternative or adjunctive treatments. Attractive and novel forms of therapy include strategies to eliminate detrimental gluten peptides from the celiac diet so that the immunogenic effect of the gluten epitopes can be neutralized, as well as strategies to block the gluten-induced inflammatory response. In the present paper, we review recent developments in the use of enzymes as additives or as processing aids in the food biotechnology industry to detoxify gluten. [ABSTRACT FROM AUTHOR]

Background: Adaptative immune repertoire diversity in vertebrate species is generated by recombination of variable (V), diversity (D) and joining (J) genes in the immunoglobulin (IG) loci of B lymphocytes and in the T cell receptor (TR) loci of T lymphocytes. These V-J and V-D-J gene rearrangements at the DNA level involve recombination signal sequences (RSS). Whereas many data exist, they are scattered in non specialized resources with different nomenclatures (eg. flat files) and are difficult to extract. Description: IMGT/GeneInfo is an online information system that provides, through a user-friendly interface, exhaustive information resulting from the complex mechanisms of T cell receptor V-J and V-DJ recombinations. T cells comprise two populations which express the αβand γδ TR, respectively. The first version of the system dealt with the Homo sapiens and Mus musculus TRA and TRB loci whose gene rearrangements allow the synthesis of the αβ TR chains. In this paper, we present the second version of IMGT/GeneInfo where we complete the database for the Homo sapiens and Mus musculus TRG and TRD loci along with the introduction of a quality control procedure for existing and new data. We also include new functionalities to the four loci analysis, giving, to date, a very informative tool which allows to work on V(D)J genes of all TR loci in both human and mouse species. IMGT/GeneInfo provides more than 59,000 rearrangement combinations with a full gene description which is freely available at http://imgt.cines.fr/ GeneInfo. Conclusion: IMGT/GeneInfo allows all TR information sequences to be in the same spot, and are now available within two computer-mouse clicks. This is useful for biologists and bioinformaticians for the study of T lymphocyte V(D)J gene rearrangements and their applications in immune response analysis. [ABSTRACT FROM AUTHOR]

This paper describes the initial appearance and distribution of mature T and B cells in the developing immune tissues of the stripe-faced dunnart ( Sminthopsis macroura) based on the use of species cross-reactive antibodies to the lymphocyte cell surface markers CD3, CD5 and CD79b. At birth no mature T or B cells were detected in the liver or bone marrow using anti-CD3, anti-CD5 or anti-CD79b antibodies. T cells were detected in the thymus with anti-CD3 by day 12 and anti-CD5 by day 50 postpartum, and T cells in the spleen were detected by day 43 and day 80 postpartum using anti-CD3 and anti-CD5, respectively. B cells were observed in the dunnart spleen by 43 days after birth. CD3- and CD79b-positive cells were detected in the lymph nodes by 50 days and CD5 by day 15 after birth, and in the gut-associated lymphoid tissues by day 50 and anti-CD5 by day 57 postpartum. The development and distribution of T and B cells in the immune tissues of dunnart pouch young is similar to that described in other marsupial species. Low numbers or absence of mature lymphocytes in immune tissues of early pouch young dunnarts further support the proposition that young marsupials are reliant on non-specific defence strategies and/or maternal strategies for a significant period of their time of development in the pouch. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) is known to alter circulating effector memory or re-expressing CD45RA+ (TemRA) T-cell numbers, but whether Epstein–Barr virus (EBV) does the same or this is amplified during a CMV and EBV co-infection is unclear. Immune cell numbers in blood of children and young, middle-aged, and senior adults (n = 336) were determined with flow cytometry, and additional multivariate linear regression, intra-group correlation, and cluster analyses were performed. Compared to non-infected controls, CMV-seropositive individuals from all age groups had more immune cell variance, and CMV+ EBV− senior adults had more late-differentiated CD4+ and CD8+ TemRA and CD4+ effector memory T-cells. EBV-seropositive children and young adults had a more equal immune cell composition than non-infected controls, and CMV− EBV+ senior adults had more intermediate/late-differentiated CD4+ TemRA and effector memory T-cells than non-infected controls. CMV and EBV co-infected young and middle-aged adults with an elevated BMI and anti-CMV antibody levels had a similar immune cell composition as senior adults, and CMV+ EBV+ middle-aged adults had more late-differentiated CD8+ TemRA, effector memory, and HLA-DR+ CD38− T-cells than CMV+ EBV− controls. This study identified changes in T-cell numbers in CMV- or EBV-seropositive individuals and that some CMV and EBV co-infected young and middle-aged adults had an aging-related T-cell phenotype. [ABSTRACT FROM AUTHOR]

Objective: The kinetics of immune responses to various SARS-CoV-2 vaccines in cancer patients were investigated. Methods: In total, 57 cancer patients who received BNT162b2-RNA or BBIBP-CorV vaccines were enrolled. Cellular and humoral immunity were assessed at three-time points, before the first vaccine dose and 14–21 days after the first and second doses. Chemiluminescent microparticle immunoassay was used to evaluate SARS-CoV-2 anti-spike IgG response, and QuantiFERON® SARS-CoV-2 kit assessed T-cell response. Results: Data showed that cancer patients' CD4+ and CD8+ T cell-median IFN-γ secretion of SARS-CoV-2 antigens increased after the first and second vaccine doses (p = 0.027 and p = 0.042). BNT162b2 vaccinees had significantly higher IFN-γ levels to CD4+ and CD8+ T cell epitopes than BBIBP-CorV vaccinees (p = 0.028). There was a positive correlation between IgG antibody titer and T cell response regardless of vaccine type (p < 0.05). Conclusions: This study is one of the first to investigate cellular and humoral immune responses to SARS-CoV-2 immunization in cancer patients on active therapy after each vaccine dose. COVID-19 immunizations helped cancer patients develop an effective immune response. Understanding the cellular and humoral immune response to COVID-19 in cancer patients undergoing active treatment is necessary to improve vaccines and avoid future SARS pandemics. [ABSTRACT FROM AUTHOR]

Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4+ and CD8+ T cells. Co-culturing CD4+ with autologous CD8+ T cells from ART-suppressed HIV+ donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8+ T cells. This trispecific antibody mediates CD4+ and CD8+ T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection. One of the main hurdles to curing HIV infection are viral reservoirs. Here, the authors develop a trispecific antibody and demonstrate its ability to simultaneously activate and target latently HIV−1 infected cells for elimination by T cells as an alternative strategy for HIV cure. [ABSTRACT FROM AUTHOR]

Bi-specific T-cell engager antibodies (BiTEs) are synthetic fusion molecules that combine multiple antibody-binding domains to induce active contact between T-cells and antigen expressing cells in the body. Blinatumomab, a CD19-CD3 BiTE is now a widely used therapy for relapsed B-cell malignancies, and similar BiTE therapeutics have shown promise for treating various other forms of cancer. The current process for new BiTE development is time consuming and costly, requiring characterization of the individual antigen binding domains, followed by bi-specific design, protein production, purification, and eventually functional screening. Here, we sought to establish a more cost-efficient approach for generating novel BiTE sequences and assessing bioactivity through a function first approach without purification. We generate a plasmid with a bi-modular structure to allow high-throughput exchange of either binding arm, enabling rapid screening of novel tumour-targeting single chain variable (scFv) domains in combination with the well-characterized OKT3 scFv CD3-targeting domain. We also demonstrate two systems for high throughput functional screening of BiTE proteins based on Jurkat T cells (referred to as BiTE-J). Using BiTE-J we evaluate four EGFRvIII-scFv sequenced in BiTE format, identifying two constructs with superior activity for redirecting T-cells against the EGFRvIII-tumour specific antigen. We also confirm activity in primary T cells, where novel EGFRvIII-BiTEs induced T cell activation and antigen selective tumor killing. We finally demonstrate similar exchange the CD3-interacting element of our bi-modular plasmid. By testing several novel CD3-targeting scFv elements for activity in EGFRvIII-targeted BiTEs, we were able to identify highly active BiTE molecules with desirable functional activity for downstream development. In summary, BiTE-J presents a low cost, high-throughput method for the rapid assessment of novel BiTE molecules without the need for purification and quantification. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 has resulted in high levels of morbidity and mortality world-wide, and severe complications can occur in older populations. Humoral immunity induced by authorized vaccines wanes within 6 months, and frequent boosts may only offer transient protection. GRT-R910 is an investigational self-amplifying mRNA (samRNA)-based SARS-CoV-2 vaccine delivering full-length Spike and selected conserved non-Spike T cell epitopes. This study reports interim analyses for a phase I open-label dose-escalation trial evaluating GRT-R910 in previously vaccinated healthy older adults (NCT05148962). Primary endpoints of safety and tolerability were assessed. Most solicited local and systemic adverse events (AEs) following GRT-R910 dosing were mild to moderate and transient, and no treatment-related serious AEs were observed. The secondary endpoint of immunogenicity was assessed via IgG binding assays, neutralization assays, interferon-gamma ELISpot, and intracellular cytokine staining. Neutralizing antibody titers against ancestral Spike and variants of concern were boosted or induced by GRT-R910 and, contrasting to authorized vaccines, persisted through at least 6 months after the booster dose. GRT-R910 increased and/or broadened functional Spike-specific T cell responses and primed functional T cell responses to conserved non-Spike epitopes. This study is limited due to small sample size, and additional data from ongoing studies will be required to corroborate these interim findings. Palmer et al. present interim findings from their clinical trial; they describe the reactogenicity and immunogenicity results of a self-amplifying mRNA SARS-CoV-2 booster vaccine within an older population (≥60 years of age). [ABSTRACT FROM AUTHOR]

With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments. Immune checkpoint inhibitors are now routinely used in cancer therapy, however, the dosage and integration into conventional cancer therapy is determined via empirical experience rather than mechanistic rationale. Here authors establish an advanced single-molecule imaging method, by with which they are directly monitoring and evaluating the effect of immune checkpoint inhibitors on T cell signaling. [ABSTRACT FROM AUTHOR]

Simple Summary: Visceral leishmaniasis is a tropical neglected disease caused by infection with Leishmania parasites. There are no human vaccines and the current drug treatments for infected patients are hampered by toxicity and the development of resistance. In our study, we have used an immunotherapeutic approach, which combines a vaccine and drug, to treat mice infected with the parasite. This involved injecting a candidate Leishmania vaccine ChimT with the adjuvant monophosphoryl lipid A (MPLA, which enhances the immune response) and a treatment drug amphotericin B (AmpB). We found that the combined immunotherapy of ChimT/MPLA/AmpB significantly reduced the number of parasites within infected internal organs of the animals and increased the production of protective antibodies. Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant reduced the inherent toxicity of the drug. In addition, the ChimT vaccine stimulated in vitro mouse white cells to kill three different Leishmania parasites that had invaded the cells. We conclude that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for Leishmania infection. Visceral leishmaniasis (VL) in the Americas is a chronic systemic disease caused by infection with Leishmania infantum parasites. The toxicity of antileishmanial drugs, long treatment course and limited efficacy are significant concerns that hamper adequate treatment against the disease. Studies have shown the promise of an immunotherapeutics approach, combining antileishmanial drugs to reduce the parasitism and vaccine immunogens to activate the host immune system. In the current study, we developed an immunotherapy using a recombinant T cell epitope-based chimeric protein, ChimT, previously shown to be protective against Leishmania infantum, with the adjuvant monophosphoryl lipid A (MPLA) and amphotericin B (AmpB) as the antileishmanial drug. BALB/c mice were infected with L. infantum stationary promastigotes and later they received saline or were treated with AmpB, MPLA, ChimT/Amp, ChimT/MPLA or ChimT/MPLA/AmpB. The combination of ChimT/MPLA/AmpB significantly reduced the parasite load in mouse organs (p < 0.05) and induced a Th1-type immune response, which was characterized by higher ratios of anti-ChimT and anti-parasite IgG2a:IgG1 antibodies, increased IFN-γ mRNA and IFN-γ and IL-12 cytokines and accompanied by lower levels of IL-4 and IL-10 cytokines, when compared to other treatments and controls (all p < 0.05). Organ toxicity was also lower with the ChimT/MPLA/AmpB immunotherapy, suggesting that the inclusion of the vaccine and adjuvant ameliorated the toxicity of AmpB to some degree. In addition, the ChimT vaccine alone stimulated in vitro murine macrophages to significantly kill three different internalized species of Leishmania parasites and to produce Th1-type cytokines into the culture supernatants. To conclude, our data suggest that the combination of ChimT/MPLA/AmpB could be considered for further studies as an immunotherapy for L. infantum infection. [ABSTRACT FROM AUTHOR]

Herd immunity achieved through mass vaccination is an effective approach to prevent contagious diseases. Nonetheless, emerging SARS-CoV-2 variants with frequent mutations largely evaded humoral immunity induced by Spike-based COVID-19 vaccines. Herein, we develop a lipid nanoparticle (LNP)-formulated mRNA-based T-cell-inducing antigen, which targeted three SARS-CoV-2 proteome regions that enriched human HLA-I epitopes (HLA-EPs). Immunization of HLA-EPs induces potent cellular responses to prevent SARS-CoV-2 infection in humanized HLA-A*02:01/DR1 and HLA-A*11:01/DR1 transgenic mice. Of note, the sequences of HLA-EPs are highly conserved among SARS-CoV-2 variants of concern. In humanized HLA-transgenic mice and female rhesus macaques, dual immunization with the LNP-formulated mRNAs encoding HLA-EPs and the receptor-binding domain of the SARS-CoV-2 B.1.351 variant (RBDbeta) is more efficacious in preventing infection of SARS-CoV-2 Beta and Omicron BA.1 variants than single immunization of LNP-RBDbeta. This study demonstrates the necessity to strengthen the vaccine effectiveness by comprehensively stimulating both humoral and cellular responses, thereby offering insight for optimizing the design of COVID-19 vaccines. The authors show that an mRNA-based T-cell-inducing antigen combined with the receptor-binding domain of the SARS-CoV-2 spike protein strengthens the COVID19 vaccine against SARS-CoV-2 variants, suggesting improved vaccine designs that comprehensively stimulate both humoral and cellular responses. [ABSTRACT FROM AUTHOR]

Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19. Lei et al. show that intranasal immunisation with their vaccine candidate is able to broadly protect mice from SARS-CoV-2 infection, including Omicron variants. [ABSTRACT FROM AUTHOR]

Kidney transplanted recipients (KTR) are at high risk of severe SARS-CoV-2 infection due to immunosuppressive therapy. Although several studies reported antibody production in KTR after vaccination, data related to immunity to the Omicron (B.1.1.529) variant are sparse. Herein, we analyzed anti-SARS-CoV-2 immune response in seven KTR and eight healthy controls after the second and third dose of the mRNA vaccine (BNT162b2). A significant increase in neutralizing antibody (nAb) titers were detected against pseudoviruses expressing the Wuhan-Hu-1 spike (S) protein after the third dose in both groups, although nAbs in KTR were lower than controls. nAbs against pseudoviruses expressing the Omicron S protein were low in both groups, with no increase after the 3rd dose in KTR. Reactivity of CD4+ T cells after boosting was observed when cells were challenged with Wuhan-Hu-1 S peptides, while Omicron S peptides were less effective in both groups. IFN-γ production was detected in KTR in response to ancestral S peptides, confirming antigen-specific T cell activation. Our study demonstrates that the 3rd mRNA dose induces T cell response against Wuhan-Hu-1 spike peptides in KTR, and an increment in the humoral immunity. Instead, humoral and cellular immunity to Omicron variant immunogenic peptides were low in both KTR and healthy vaccinated subjects. [ABSTRACT FROM AUTHOR]

This article presents abstracts for various research papers to be presented in the European Society for Dermatological Research's symposium on September 26-28, 1997. These research papers pertain to subjects like the eortic classification for primary cutaneous lymphomas, different prognosis between cutaneous and systemic lymphoproliferative disorders, parapsoriasis and early cutaneous T cell lymphoma, immunoglobulin gene rearrangement of pseudo B-cell lymphomas and prognostic significance of polymerase chain reaction detectable dominant T lymphocyte clones.

This paper describes the spontaneous occurrence of an autoimmune uveoretinitis in nude (nu/nu) mice reconstituted when 4 weeks old by the grafting of rat embryonic thymus. The uveoretinitis was characterized histologically by progressive loss of the photoreceptor layer, observed in 4.0, 17.6, 42.9% and 71.4% of such mice at 3, 5, 7 and 12 months of age, respectively. Mice with uveoretinitis were shown to have serum IgG antibody reactive by indirect immunofluorescence with retinal photoreceptors, and with interphotoreceptor retinoid-binding protein (IRBP), but not retinal S-antigen, by immunoblotting and ELISA. A uveoretinitis could be adoptively transferred to syngeneic ungrafted nude mice by splenic CD4+ T cells from diseased animals. This is the first experimental model of a (T cell mediated) autoimmune uveoretinitis which develops spontaneously and which is not dependent upon deliberate sensitization with retinal antigens and adjuvants. [ABSTRACT FROM AUTHOR]

Peripheral blood mononuclear cells from patients with Sjögren's Syndrome spontaneously secrete autoantibodies to the La antigen when cultured in vitro. This paper reports that specific IgG autoantibody production in vitro is suppressed by pre-treatment of CD8+ enriched T cells with rabbit polyclonal antibodies to idiotypes borne by circulating autologous anti-La antibodies. Treatment of this T cell subpopulation with anti-idiotypes specific for circulating anti-La antibodies from other patients or for anti-DNA antibodies was without effect on anti-La antibody production. Similarly anti-La anti-idiotypes had no effect on the production of autoantibodies to other ribonucleoprotein antigens such as nRNP/Sm. These data show that CD8+ T cells are the main targets for anti-idiotypic control in vitro. We suggest that the relative deficit of these cells, plus a surfeit of CD4+ T cells at the site of the pathological lesion within the salivary gland permits localized production of autoantibodies. Thus, dysregulation of the idiotypic network could contribute to the pathogenesis of Sjögren's Syndrome. [ABSTRACT FROM AUTHOR]

The antigen-induced DNA synthesis in vitro in lymphocytes from patients with acute Plasmodium falciparum malaria was investigated. The patients and healthy controls from Sweden or Colombia were the same as those studied in the accompanying paper (Troye-Blomberg el al., 1983). The malarial antigens used were sonicated membrane preparations or purified and concentrated supernatants from in vitro cultures of P. facliparum, similar preparations derived from normal human erythrocytes served as control antigen. In the patients' lymphocytes P. falciparum antigens induced a weak or moderate but significant stimulation of DNA synthesis, peaking after 3-4 days of incubation. This early response was specific for P. faleiparum since it was not obtained with lymphocytes from healthy donors nor with those from patients with acute P. vivax or P. ovale malaria. No antigen-induced response was seen in about half of the P.falciparum patients. However in a few negative eases, available for consecutive testing, positive reactions were seen with lymphocytes taken 2 weeks after infection when the blood of these patients was free of parasites. The early response induced in patients' lymphocytes to the P. falciparum antigens was not obtained with RBC antigen, however, these preparations frequently induced a response rising to significant levels later during incubation (day 5-6)- Similar delayed responses were obtained when either- patients' or control donors' lymphocytes were exposed to the P. falciparum antigens. This indicates that both the RBC and the parasite preparations contained mitogenic substances affecting human lymphocytes in general and easily obscuring the P, falciparum specific responses seen only in the patients. This latter response was relatively low and short lived, suggesting that it reflected a secondary in vitro stimulation of in vivo primed lymphocytes and that it was regulated by suppressor mechanisms. [ABSTRACT FROM AUTHOR]