Robust Immune Response Research Articles

TLR7/8/9 agonists and low-dose cisplatin synergistically promotes tertiary lymphatic structure formation and antitumor immunity

In situ vaccination (ISV) triggers antitumor immune responses using the patient’s own cancer antigens, yet limited neoantigen release hampers its efficacy. Our novel combination therapy involves low-dose local cisplatin followed by ISV with a TLR7/8/9 agonist formulation (CR108), in which CR108 boosts and sustains the antitumor responses induced by the cisplatin-released neoantigens. In mouse models, the cisplatin+CR108 combination significantly outperformed cisplatin or CR108 alone in abrogating established 4T1 and B16 tumors. The synergistic antitumor effects of cisplatin and CR108 were accompanied by markedly increased tumor tertiary lymphatic structures (TLS) formation, higher levels of type I and III interferons and TNF-α in serum, augmented T and B lymphocyte infiltration, antigen-presenting cell activation, as well as reduced functionally of exhausted T cells. Single-cell sequencing analysis uncovered a potential pathway for TLS to serve as a reservoir for functional antitumor effector T cells. Furthermore, cisplatin+CR108 combo therapy, but neither cisplatin nor CR108 alone, effectively inhibited the growth of treated 4T-1 tumor in an effector T cell-dependent manner. Notably, the combo therapy also suppressed the growth of distant untreated 4T-1 tumors, demonstrating systemic antitumor effects. Moreover, combo-therapy led to full regression of 4T-1 tumors in a large percentage of mice, who became strongly resistant to secondary tumor challenge, a clear indication of antitumor immunological memory. The cisplatin+CR108 combo therapy holds promise in converting “cold” tumors into “hot” ones and eliciting robust antitumor immune responses in vivo.

The Development of a Novel Broad-Spectrum Influenza Polypeptide Vaccine Based on Multi-Epitope Tandem Sequences

Background: Polypeptide vaccines have the potential to improve immune responses by targeting conserved and weakly immunogenic regions in antigens. This study aimed to identify and evaluate the efficacy of a novel influenza universal vaccine candidate consisting of multiple polypeptides derived from highly conserved regions of influenza virus proteins hemagglutinin (HA), neuraminidase (NA), and matrix protein 2 (M2). Methods: Immunoinformatics tools were used to screen conserved epitopes from different influenza virus subtypes (H1N1, H3N2, H5N1, H7N9, H9N2, and IBV). A polypeptide vaccine, P125-H, was constructed by linking multiple epitopes using Ii-Key technology. The immunogenicity of P125-H was assessed in mice using MF59-adjuvanted P125-H via intraperitoneal injection. Hemagglutination inhibition (HI) and neutralizing antibody responses were measured, along with IFN-γ levels in spleen lymphocytes. Protective efficacy was evaluated using viral challenge with lethal doses of H1N1 and H7N9. Results: Mice immunized with P125-H generated high levels of HI and neutralizing antibodies against multiple influenza strains. IFN-γ production was significantly elevated in spleen lymphocytes upon stimulation with the vaccine. P125-H protected mice from influenza infection, reducing weight loss and the viral load in the lungs, mitigating lung pathology, and decreasing mortality. Conclusions: The P125-H vaccine induced broad cross-protection against multiple influenza strains and elicited robust immune responses. It demonstrates strong potential as a candidate for a universal influenza vaccine.

Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy.

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and the subsequent release of mitochondrial DNA (mtDNA), which is anticipated to activate the cGAS-STING pathway, thereby augmenting the antitumor immune response. However, challenges lie in effectively triggering pyroptosis in cancer cells and subsequently enhancing the cGAS-STING activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators of cobalt fluoride (CoF2) nanocatalysts for catalytic metalloimmunotherapy. CoF2 nanocatalysts with a semiconductor structure and enzyme-like activity generated a substantial amount of reactive oxygen species (ROS) under stimulation by endogenous H2O2 and exogenous ultrasound. Importantly, we discovered that Co-based nanomaterials themselves induce pyroptosis in cancer cells. Therefore, CoF2 nanocatalysts initially acted as pyroptosis inducers, triggering caspase-1/GSDMD-dependent pyroptosis in cancer cells via Co2+ and ROS, leading to mtDNA release. Subsequently, CoF2 nanocatalysts were further utilized as intelligent STING agonists that were specifically capable of detecting mtDNA and augmenting the activation of the cGAS-STING pathway. These cascade events triggered a robust immune response, effectively modulating the immunosuppressive tumor microenvironment into an immune-supportive state, thereby providing favorable support for antitumor therapy. This innovative strategy not only significantly impeded the growth of the primary tumor but also elicited an immune response to further augment the efficacy of immune checkpoint inhibitors in preventing distant tumor progression. Overall, this study proposed a self-cascade strategy for activating and amplifying the cGAS-STING pathway with specificity mediated by pyroptosis, representing a valuable avenue for future cancer catalytic metalloimmunotherapy.

A synthetic cyclic peptide for promoting antigen presentation and immune activation

Cyclic peptides are often used as scaffolds for the multivalent presentation of drug molecules due to their structural stability and constrained conformation. We identified a cyclic deca-peptide incorporating lipoamino acids for delivering T helper and B cell epitopes against group A Streptococcus (GAS), eliciting robust humoral immune responses. In this study, we assessed the function-immunogenicity relationship of the multi-component vaccine candidate (referred to as VC-13) to elucidate a mechanism of action. We identified a potential universal delivery platform, not only capable of adjuvanting different peptide epitopes (e.g., NS1 and 88/30 from group A Streptococcus, gonadotropin hormone releasing hormone [GnRH]), but also protein antigens (e.g., bovine serum albumin [BSA], receptor binding domain (RBD) of the SARS-CoV-2 protein responsible for COVID-19 infection [SARS-CoV-2 RBD]) and small molecular haptens (e.g., cocaine). All vaccine candidates self-assembled into sub-500 nm nanoparticles and induced high antigen-specific systemic IgG titers and opsonic potential compared to the antigen co-administered with a commercial adjuvant, complete Freund’s adjuvant. Notably, presence of the cyclic decapeptide in this vaccine increased accumulation in the draining inguinal lymph nodes, facilitating cellular uptake of peptide antigens. Furthermore, the lipoamino acid promoted dendritic cell activation, acting as both toll-like receptors 2 and 4 -targeting moiety. Our study revealed the importance of the cyclic decapeptide and lipoamino acid presence in antigen presentation and immune response activation, leading onto the development of a fully synthetic, self-assembled, and promising platform for the delivery of subunit vaccines and anti-drug vaccines.

PROTAR Vaccine 2.0 generates influenza vaccines by degrading multiple viral proteins.

Manipulating viral protein stability using the cellular ubiquitin-proteasome system (UPS) represents a promising approach for developing live-attenuated vaccines. The first-generation proteolysis-targeting (PROTAR) vaccine had limitations, as it incorporates proteasome-targeting degrons (PTDs) at only the terminal ends of viral proteins, potentially restricting its broad application. Here we developed the next-generation PROTAR vaccine approach, referred to as PROTAR 2.0, which enabled flexible incorporation of PTDs at various genomic loci of influenza viruses, including internal regions and terminal ends. The PROTAR 2.0 influenza viruses maintained efficient replication in UPS-deficient cells for large-scale production but were attenuated by PTD-mediated proteasomal degradation of viral proteins in conventional cells. Incorporation of multiple PTDs into one virus generated optimized PROTAR 2.0 vaccine candidates. In animal models, PROTAR 2.0 vaccine candidates were highly attenuated and a single-dose intranasal immunization induced robust and broad immune responses that provided complete cross-reactive protection against both homologous and heterologous viral challenges.

Strategic and Technical Considerations in Manufacturing Viral Vector Vaccines for the Biomedical Advanced Research and Development Authority Threats

Over the past few decades, the world has seen a considerable uptick in the number of new and emerging infectious disease outbreaks. The development of new vaccines, vaccine technologies, and platforms are critical to enhance our preparedness for biological threats and prevent future pandemics. Viral vectors can be an important tool in the repertoire of technologies available to develop effective vaccines against new and emerging infectious diseases. In many instances, vaccines may be needed in a reactive scenario, requiring technologies than can elicit rapid and robust immune responses with a single dose. Here, we discuss how viral vector vaccines are utilized in a vaccine portfolio for priority biological threats, some of the challenges in manufacturing viral vector vaccines, the need to strengthen live virus manufacturing capabilities, and future opportunities to capitalize on the use of viral vectors to improve the sustainability of the Biomedical Advanced Research and Development Authority’s vaccine portfolio.

The Role of the Immune Response to Helicobacter pylori Antigens and Its Relevance in Gastric Disorders

Helicobacter pylori (H.p.) is a Gram-negative bacterium endowed with gastric tropism. H.p. infection is widely spread throughout the world, accounting for various pathologies, such as peptic ulcer, gastric cancer, mucosa-associated lymphoid tissue lymphoma, and extra-gastric manifestations. This bacterium possesses several virulence factors, e.g., lipopolysaccharides (LPS), the toxins CagA and VacA, and adhesins, which elicit a robust immune response during the initial phase of the infection. Of note, the lipid A moiety of the LPS exhibits a lower endotoxic potency than that of other LPSs, thus facilitating infection through a mechanism of immune escape. H.p. colonization of the gastric mucosa induces an initial protective immune response with innate immune cells, e.g., neutrophils, monocytes, and macrophages, which engulf and kill bacteria. Moreover, the same cells, along with gastric epithelial cells, secrete cytokines and chemokines, which recruit T cells [T helper (h)1 and Th17 cells] to the site of infection, thus leading to H.p. eradication. In a large subset of individuals, the perturbation of such an immune equilibrium leads to a harmful response, with an expansion of T regulatory (TREG) cells, which suppress the protective immune response. In fact, TREG cells, via the production of interleukin (IL)-10, downregulate Th1- and Th17-related cytokines, thus allowing H.p. survival and the perpetuation of inflammation. As far as the humoral immune response is concerned, B cells, upon H.p. stimulation, produce autoreactive antibodies, and IgG anti-Lex antibodies are harmful to the gastric mucosa. In this review, the structure and function of H.p. antigenic components and immune mechanisms elicited by this bacterium will be described in relation to gastric damage.

Innovative epitopes in Staphylococcal Protein-A an immuno-informatics approach to combat MDR-MRSA infections

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge in clinical environments due to its resistance to standard antibiotics. Staphylococcal Protein A (SpA), a crucial virulence factor of MRSA, undermines host immune responses, making it an attractive target for vaccine development. This study aimed to identify potential epitopes within SpA that could elicit robust immune responses, ultimately contributing to the combat against multidrug-resistant (MDR) MRSA.MethodsThe SpA protein sequence was retrieved from the UniProt database, with various bioinformatics tools employed for epitope prediction. T-cell epitopes were identified using the Tepitool server, focusing on high-affinity interactions with prevalent human leukocyte antigens (HLAs). B-cell epitopes were predicted using the BepiPred tool. Predicted epitopes underwent docking studies with HLA molecules to evaluate binding properties. In-silico analyses confirmed the antigenicity, promiscuity, and non-glycosylated nature of the selected epitopes.ResultsSeveral T and B cell epitopes within SpA were identified, showcasing high binding affinities and extensive population coverage. A multi-epitope vaccine construct, linked by synthetic linkers and an adjuvant, was modelled, refined, and validated through various bioinformatics assessments. The vaccine candidate was subsequently docked with Toll-like receptor 4 (TLR-4) to evaluate its potential for immunogenicity.ConclusionThis study lays the groundwork for developing epitope-based vaccines targeting SpA in MRSA, identifying promising candidates for experimental validation and contributing to innovative immunotherapeutic strategies against MRSA infections.

Comprehensive Analysis of the Immune Response to SARS-CoV-2 Epitopes: Unveiling Potential Targets for Vaccine Development

SARS-CoV-2 continues to be a major global health threat. In this study, we performed a comprehensive meta-analysis on the epitopes of SARS-CoV-2, revealing its immunological landscape. Furthermore, using Shannon entropy for sequence conservation analysis and structural network-based methods identified candidate epitopes that are highly conserved and evolutionarily constrained in SARS-CoV-2 and other zoonotic coronaviruses. Finally, the population coverage of T cell epitopes was analyzed. The results highlighted regions within each SARS-CoV-2 protein where the immunological activity of antibodies, CD4+, and CD8+ T cell responses was predominantly concentrated. Sequence-based correlation analysis found that epitopes recognized by B cells and CD4+ T cells showed a positive correlation with high viral variability, and these high variability regions were typically linked to robust immune responses. Conversely, epitopes recognized by CD8+ T cells exhibited a negative correlation with high variability. From a structural network degree perspective, no clear correlation was identified between B cell antibody epitopes and CD4+ T cell reactivity with the degree of residue network connectivity. However, a significant positive correlation was observed between CD8+ T cell reactivity and the degree of residue network connectivity. By integrating sequence Shannon entropy and structural network correlation analysis, we pinpointed highly conserved and evolutionarily constrained SARS-CoV-2 candidate epitopes. Furthermore, we utilized immunoinformatics to assess the conservation of SARS-CoV-2 within coronaviruses and the population coverage of these epitopes. Our analysis uncovered key immune responses linked to preventing viral infection and viral clearance, emphasized areas of interest for broad-spectrum SARS-CoV-2 vaccine development, and offered insights for future research and clinical applications.

Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals.

Vesicles play critical roles in cellular materials storage and signal transportation, even in the formation of organelles and cells. Natural vesicles are composed of a lipid layer that forms a membrane for the enclosure of substances inside. Here we report a coacervate vesicle formed by the liquid-liquid phase separation of cholesterol-modified DNA and histones. Unlike a phospholipid-based membrane-bounded vesicle, a coacervate vesicle lacks a membrane structure on the surface and is organized with a high-density liquid layer and a water-filled cavity. Through a straightforward coacervation process, we demonstrate that various biological agents, including virus particles, mRNA, cytokines and peptides, can be innocuously and directly enriched in the liquid phase. In contrast to the droplet-like coacervates that are prone to aggregation challenges, coacervate vesicles display superior kinetic stability, positioning them as a versatile delivery vehicle for biopharmaceuticals. We validate that incorporating oncolytic viruses into these coacervate vesicles endows them with potent oncolytic efficacy and elicits robust anti-tumour immune responses in mouse models.

Tumor Vaccine Exploiting Membranes with Influenza Virus-Induced Immunogenic Cell Death to Decorate Polylactic Coglycolic Acid Nanoparticles.

Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.

MRNA vaccines with RBD mutations have broad-spectrum activity against SARS-CoV-2 variants in mice

The emergence of SARS-CoV-2 variants with defined mutations that enhance pathogenicity or facilitate immune evasion has resulted in a continual decline in the protective efficacy of existing vaccines. Therefore, there is a pressing need for a vaccine capable of combating future variants. In this study, we designed new mRNA vaccines, BSCoV05 and BSCoV06, and generated point mutations in the receptor-binding domain (RBD) of the original Wuhan strain to increase their broad-spectrum antiviral activity. Additionally, we used the BA.1 RBD as a control. Both vaccines elicited a robust immune response in BALB/c and K18-hACE2 mice, generating high levels of specific binding antibodies against the BA.2 RBD. Moreover, all three vaccines induced neutralizing antibodies against the prototype viral strain and relevant variants, including the Alpha and Beta strains and the Omicron variants BA.1, BA.2, BA.5, XBB.1.5, XBB.1.16, EG.5.1, and EG.5.1.1, with BSCoV06 demonstrating broader neutralizing antibody activity. Both BSCoV05 and BSCoV06 also elicited a cellular immune response. After the challenge, both BSCoV05 and BSCOV06 provided protection against the EG.5.1 strain in both mouse strains. Therefore, these two vaccines merit further evaluation in nonhuman primates, and this vaccine design strategy should be explored for its potential application in combating future SARS-CoV-2 variants, offering valuable insights into broad-spectrum vaccine development.

Evaluating small extracellular vesicle-based vaccination across heterologous Salmonella strains isolated from wastewater.

Salmonella infections pose significant public health challenges worldwide. The diversity of Salmonella strains, particularly those isolated from environmental and clinical sources, necessitates innovative approaches to prevention and treatment. Previous research has shown that small extracellular vesicles (sEVs) produced by macrophages during Salmonella Typhimurium infection can induce robust immune responses when used as a vaccine, offering complete protection in systemic infection models. In this study, we isolated 120 Salmonella strains from qPCR invA-positive wastewater samples collected in Gainesville, FL. These strains underwent enrichment, selection, and biochemical confirmation, followed by serotyping and whole genome sequencing. Two isolates, Salmonella enterica subsp. diarizonae (Diarizonae) and S. enterica serovar Enteritidis, were selected for further analysis based on community prevalence and clinical severity. We also assessed the ability of sEVs produced by S. Typhimurium-infected macrophages to induce immune responses against these heterologous and circulating strains in mice. Immunization with sEVs induced robust antigen-specific SIgA and IgG responses against S. Typhimurium, Enteritidis, and Diarizonae, with high titers observed in sera and fecal samples. Proteomic analysis revealed differential expression of proteins in these strains, including antigenic proteins present in sEVs such as OmpA, FliC, or OmpD. Moreover, this study highlights the role of wastewater-based epidemiology (WBE) as a tool for environmental surveillance, offering a complementary perspective on Salmonella dynamics within a population. Integrating WBE with traditional surveillance methods, along with the promising results of sEV-based vaccination, provides a pragmatic strategy for developing effective preventative measures against Salmonella infections, addressing the diversity of non-typhoidal Salmonella strains.

Truncated NS1 Influenza A Virus Induces a Robust Antigen-Specific Tissue-Resident T-Cell Response and Promotes Inducible Bronchus-Associated Lymphoid Tissue Formation in Mice

Background: Influenza viruses with truncated NS1 proteins show promise as viral vectors and candidates for mucosal universal influenza vaccines. These mutant NS1 viruses, which lack the N-terminal half of the NS1 protein (124 a.a.), are unable to antagonise the innate immune response. This creates a self-adjuvant effect enhancing heterologous protection by inducing a robust CD8+ T-cell response together with immunoregulatory mechanisms. However, the effects of NS1 modifications on T-follicular helper (Tfh) and B-cell responses remain less understood. Methods: C57bl/6 mice were immunised intranasally with 10 μL of either an influenza virus containing a truncated NS1 protein (PR8/NS124), a cold-adapted influenza virus with a full-length NS1 (caPR8/NSfull), or a wild-type virus (PR8/NSfull). Immune responses were assessed on days 8 and 28 post-immunisation by flow cytometry, ELISA, and HAI assay. Results: In this study, we demonstrate that intranasal immunisation with PR8/NS124 significantly increases tissue-resident CD4+ and CD8+ T cells in the lungs and activates Tfh cells in regional lymph nodes as early as day 8 post-immunisation. These effects are not observed in mice immunised with caPR8/NSfull or PR8/NSfull. Notably, PR8/NS124 immunisation also leads to the development of inducible bronchus-associated lymphoid tissue (iBALT) in the lungs by day 28, characterised by the presence of antigen-specific Tfh cells and GL7+Fas+ germinal centre B cells. Conclusions: Our findings further underscore the potential of NS1-truncated influenza viruses to drive robust mucosal immune responses and enhance vaccine efficacy.

Development of a novel multi-epitope subunit mRNA vaccine candidate to combat Acinetobacter baumannii

Acinetobacter baumannii, an opportunistic bacterium prevalent in various environment, is a significant cause of nosocomial infections in ICUs. As the causative agent of pneumonia, septicemia, and meningitis, A. baumannii typically exhibits multidrug resistance and is associated with poor prognosis, thus led to a challenge for researchers in developing new treatment and prevention methods. This study involved the development of a novel multi-epitope mRNA vaccine for A. baumannii and validation of in silico approaches was conducted. We screened 11 immunodominant epitopes for cytotoxic T cells, 5 for helper T cells, and 10 for Linear B-cell based on promising candidate proteins omp33-36, ompA and ompW, the selection of these three proteins is based on reverse vaccinology screening and previous work by other researchers. All predicted epitopes demonstrated strong antigenicity, immunogenicity without posing any potential harm to humans. Additionally, high conservancy is required to cover different strains. All epitopes, as well as adjuvants, were constructed into a final vaccine, which was further assessed by calculating its physicochemical properties. Next, we docked the vaccine protein with immune receptors and analyzed the complexes with dynamic simulations to evaluate its affinity to receptors. At last, the constructed sequence is translated to an mRNA sequence. The results indicated the constructed vaccine is capability of eliciting robust humoral and cellular immune responses, making it a promising candidate for protection against the targeted pathogen.

A phase I clinical trial of intrahepatic artery delivery of TG6002 in combination with oral 5-fluorocytosine in patients with liver-dominant metastatic colorectal cancer.

Effective treatment for patients with metastatic cancer is limited, particularly for colorectal cancer patients with metastatic liver lesions (mCRC), where accessibility to numerous tumours is essential for favourable clinical outcomes. Oncolytic viruses (OVs) selectively replicate in cancer cells; however, direct targeting of inaccessible lesions is limited when using conventional intravenous or intratumoural administration routes. We conducted a multi-centre, dose-escalation, phase I study of vaccinia virus, TG6002, via intrahepatic artery (IHA) delivery in combination with the oral pro-drug 5-fluorocytosine to fifteen mCRC patients. Successful IHA delivery of replication-competent TG6002 was achieved, as demonstrated by virus within tumour biopsies. Functional transcription of the FCU1 transgene indicates viral replication within the tumour, with higher plasma 5-fluorouracil associated with patients receiving the highest dose of TG6002. IHA delivery of TG6002 correlated with a robust systemic peripheral immune response to virus with activation of peripheral blood mononuclear cells, associated with a proinflammatory cytokine response and release of calreticulin, potentially indicating immunogenic cell death. Gene Ontology analyses of differentially-expressed genes reveal a significant immune response at the transcriptional level in response to treatment. Moreover, an increase in the number and frequency of T-cell receptor clones against both cancer- and neo-antigens, with elevated functional activity, may be associated with improved anti-cancer activity. Despite these findings, no clinical efficacy was observed. In summary, these data demonstrate delivery of OV to tumour via IHA administration, associated with viral replication and significant peripheral immune activation. Collectively, the data supports the need for future studies using IHA administration of OVs.

Mpox virus (MPXV): comprehensive analysis of pandemic risks, pathophysiology, treatments, and mRNA vaccine development.

Mpox, formerly known as monkeypox, is a zoonotic disease caused by the Mpox virus (MPXV), which has recently attracted global attention due to its potential for widespread outbreaks. Initially identified in 1958, MPXV primarily spreads to humans through contact with infected wild animals, particularly rodents. Historically confined to Africa, the virus has expanded beyond endemic regions, with notable outbreaks in Europe and North America in 2022, especially among men who have sex with men (MSM). The World Health Organization (WHO) has declared the current Mpox outbreak a Public Health Emergency of International Concern. This review explores the epidemiology, pathophysiology, and clinical manifestations of MPXV, along with current treatment strategies and the role of mRNA vaccines. It emphasizes the importance of understanding the changing dynamics of Mpox transmission, which are influenced by factors such as waning immunity from smallpox vaccinations and increased global interconnectedness. The potential for developing multi-epitope vaccines that can stimulate robust immune responses is highlighted, showcasing how bioinformatics can facilitate the identification of immunogenic antigens. Continued research and investment in vaccine development are crucial to address the urgent need for effective candidates that can protect at-risk populations. In summary, this review underscores the necessity for proactive public health measures and collaborative efforts among healthcare authorities, researchers, and communities to mitigate the impact of Mpox and enhance global preparedness for future outbreaks.

Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS-STING Activation for Bidirectional Synergistic Hydrogen-Immunotherapy.

The cGAS-STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS-STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid-phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS-STING activation for bidirectional synergistic H2-immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H2 gas and Mn2+. MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.

NLR-mediated antiviral immunity in plants.

Plant viruses cause substantial agricultural devastation and economic losses worldwide. Plant nucleotide-binding domain leucine-rich repeat receptors (NLRs) play a pivotal role in detecting viral infection and activating robust immune responses. Recent advances, including the elucidation of the interaction mechanisms between NLRs and pathogen effectors, the discovery of helper NLRs, and the resolution of the ZAR1 resistosome structure, have significantly deepened our understanding of NLR-mediated immune responses, marking a new era in NLR research. In this scenario, significant progress has been made in the study of NLR-mediated antiviral immunity. This review comprehensively summarizes the progress made in plant antiviral NLR research over the past decades, with a focus on NLR recognition of viral pathogen effectors, NLR activation and regulation, downstream immune signaling, and the engineering of NLRs.

Safety and Immunogenicity of the Tetravalent Recombinant COVID-19 Protein Vaccine SCTV01E in Children and Adolescents Aged 3 to 17 Years: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial

Background: SCTV01E is a tetravalent recombinant COVID-19 vaccine authorized for emergency use in China for adults 18 years and older but not for those under 18. Objective: This Phase 2 trial assessed the safety and immunogenicity of SCTV01E in healthy children and adolescents aged 3 to 17 years, to establish immunobridging with that observed in adults from the efficacy pivotal trial (NCT05308576). Methods: Participants were randomly assigned to receive either 30 µg of SCTV01E or a placebo. Primary endpoints were safety and immunogenicity focused on the geometric mean titer (GMT) and seroresponse rate (SRR) of neutralizing antibodies (nAb) against Omicron BA.5. Results: In total, 268 participants (214 SCTV01E vs. 54 placebo) were included in the safety analysis, with 241 participants (191 vs. 50) in the immunogenicity analysis. Overall, 127 (59.3%) participants receiving SCTV01E and 9 (16.7%) receiving a placebo reported adverse events (AEs), most of which were Grade 1 or 2. No serious adverse events (SAEs) or adverse events of special interest (AESIs) were reported. In the immunogenicity bridging analysis, data from 95 youths were compared with data from 188 adults; the geometric mean ratio (GMR) of the titers was 8.78 (95% CI: 6.05–12.74, p < 0.001), with the lower bound of the 95% CI exceeding 0.67. The difference in the SRR was 6.34% (95% CI: 0.93–11.22%) (p = 0.029), and the lower bound of the 95%CI was >−5%, indicating superiority. Conclusions: SCTV01E was found to be safe and well tolerated in children and adolescents, generating a robust immune response against Omicron BA.5. This supports its potential use in younger populations.