Search Results (26)

We propose the Clustered Link-Prediction SEIRS model with Temporal Node Activation (CLP-SEIRS-T), a novel epidemiological framework that integrates community structure, link prediction, and temporal activation schedules to simulate malware propagation in urban communication networks. Unlike traditional static or homogeneous models, our approach captures the heterogeneous community structure of the network (modular connectivity), along with evolving connectivity (emergent links) and periodic device-usage patterns (online/offline cycles), providing a more realistic portrayal of how computer viruses spread. Simulation results demonstrate that strong community modularity and intermittent connectivity significantly slow and localize outbreaks. For instance, when devices operate on staggered duty cycles (asynchronous online schedules), malware transmission is fragmented into multiple smaller waves with lower peaks, often confining infections to isolated communities. In contrast, near-continuous and synchronized connectivity produces rapid, widespread contagion akin to classic epidemic models, overcoming community boundaries and infecting the majority of nodes in a single wave. Furthermore, by incorporating a common-neighbor link-prediction mechanism, CLP-SEIRS-T accounts for future connections that can bridge otherwise disconnected clusters. This inclusion significantly increases the reach and persistence of malware spread, suggesting that ignoring evolving network topology may underestimate outbreak risk. Our findings underscore the importance of considering temporal usage patterns and network evolution in malware epidemiology. The proposed model not only elucidates how timing and community structure can flatten or exacerbate infection curves, but also offers practical insights for enhancing the resilience of urban communication networks—such as staggering device online schedules, limiting inter-community links, and anticipating new connections—to better contain fast-spreading cyber threats. Full article

Background: Respiratory viral infections such as influenza, COVID-19, and respiratory syncytial virus (RSV) are considered as major public health threats in Africa. Despite global advancements in vaccine development, persistent inequities in access, delivery infrastructure, and public trust limit the continent’s capacity to control these diseases effectively. This review aimed at providing insights on challenges, efforts, impacts, and opportunities for the future related to vaccination against respiratory viral infections in Africa. Methods: This narrative review synthesizes the peer-reviewed literature and global health reports to examine vaccination efforts against respiratory viruses in Africa. The analysis focuses on disease burden, vaccine coverage, barriers to uptake, enabling factors, progress in local vaccine production, and strategies for integrating vaccines into national immunization programs (NIPs). Results: Respiratory vaccines have significantly reduced hospitalizations and mortality among high-risk groups in African countries. Nonetheless, key challenges, including limited cold chain capacity, vaccine hesitancy, donor-reliant supply chains, and under-resourced health systems, continue to undermine vaccine delivery. Successful interventions include community mobilization, use of mobile health technologies, and leveraging existing immunization platforms. Emerging initiatives in local vaccine manufacturing, including Rwanda’s modular mRNA facility and Senegal’s Institut Pasteur, signal a shift toward regional self-reliance. Conclusions: Maximizing the impact of respiratory vaccines in Africa requires a multifaceted strategy: integrating vaccines into NIPs, strengthening domestic production, expanding cold chain and digital infrastructure, and addressing sociocultural barriers through community-driven communication. These efforts are essential to achieving vaccine equity, health resilience, and pandemic preparedness across the continent. Full article

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article

Background/Objectives: Vaccination remains the most effective means of preventing influenza virus infections. However, the continuous antigenic drift and shift of influenza viruses lead to a reduced efficacy of the existing vaccines, necessitating vaccines capable of broad protection. Methods: To address this, we developed a modular vaccine strategy pairing a clinical-stage adjuvanted recombinant hemagglutinin (HA) vaccine (SCVC101) with OMN, a heptameric nanoparticle displaying conserved influenza A virus T-cell epitopes from nucleoprotein (NP) and matrix 2 ectodomain (M2e). Results: OMN induced cross-reactive M2e-specific antibodies, binding to diverse influenza A subtypes. Critically, the co-administration of OMN with SCVC101 enhanced cellular immunity and cross-protection without diminishing HA-induced humoral responses. Conclusions: This dual-antigen delivery system enables annual HA component updates, aligned with WHO recommendations, while the conserved OMN nanoparticle acts as a universal booster, leveraging existing production infrastructure. This approach offers a promising strategy for improving the influenza vaccine’s efficacy against emerging viral variants. Full article

In an attempt to explore the RNA viromes of two German rivers, we searched the virus particle contents of one 50 L water sample each from the Teltow Canal and the Havel River for viruses assumed to infect invertebrates. More than 330 complete and partial virus genomes up to a length of 37 kb were identified, with noda-like and reo-like viruses being most abundant, followed by bunya-like and birna-like viruses. Viruses related to the Permutotetraviridae, Nidovirales, Flaviviridae, Rhabdoviridae and Chuviridae as well as the unclassified Jῑngmén virus and Negev virus groups were also present. The results indicate a broad extent of recombinant virus genomes, supporting the concept of the modularity of eukaryotic viruses. For example, novel combinations of genes encoding replicase and structural proteins with a jellyroll fold have been observed. Less than 35 viruses could be assigned to existing virus genera. These are (i) an avian deltacoronavirus which was represented by only one short contig, albeit with 98% similarity, (ii) a seadornavirus and a rotavirus, and (iii) some 30 nodaviruses. All remaining viruses are novel and too diverse for accommodation in existing genera. Many of the virus genomes exhibit ORFans encoding hypothetical proteins of up to 2000 amino acids without conserved protein domains. Full article

Vesicular stomatitis virus (VSV) is a prototype RNA virus that has been instrumental in advancing our understanding of viral molecular biology and has applications in vaccine development, cancer therapy, antiviral screening, and more. Current VSV genome plasmids for purchase or contract virus services provide limited options for modification, restricted to predefined cloning sites and insert locations. Improved methods and tools to engineer VSV will unlock further insights into long-standing virology questions and new opportunities for innovative therapies. Here, we report the design and construction of a full-length VSV genome. The 11,161 base pair synthetic VSV (synVSV) was assembled from four modularized DNA fragments. Following rescue and titration, phenotypic analysis showed no significant differences between natural and synthetic viruses. To demonstrate the utility of a synthetic virology platform, we then engineered VSV with a foreign glycoprotein, a common use case for studying viral entry and developing anti-virals. To show the freedom of design afforded by this platform, we then modified the genome of VSV by rearranging the gene order, switching the positions of VSV-P and VSV-M genes. This work represents a significant technical advance, providing a flexible, cost-efficient platform for the rapid construction of VSV genomes, facilitating the development of innovative therapies. Full article

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, the mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors integrating Tag/Catcher proteins at specific locales on the Ad capsid proteins, allowing us to anchor mRNA to the surface of engineered Ad viruses. In proof-of-concept studies, the Ad-mRNA platform successfully mediated mRNA delivery and could be optimized via the highly flexible modular design of both the Ad-mRNA and protein bioconjugation systems. Full article

Developing recombinant proteins as nasal vaccines for inducing systemic and mucosal immunity against respiratory viruses is promising. However, additional adjuvants are required to overcome the low immunogenicity of protein antigens. Here, a self-adjuvanted protein-RNA ribonucleoprotein vaccine was developed and found to be an effective nasal vaccine in mice and the SARS-CoV-2 infection model. The vaccine consisted of spike RBD (as an antigen), nucleoprotein (as an adaptor), and ssRNA (as an adjuvant and RNA scaffold). This combination robustly induced mucosal IgA, neutralizing antibodies and activated multifunctional T-cells, while also providing sterilizing immunity against live virus challenge. In addition, high-resolution scRNA-seq analysis highlighted airway-resident immune cells profile during prime-boost immunization. The vaccine also possesses modularity (antigen/adaptor/RNA scaffold) and can be made to target other viruses. This protein-RNA ribonucleoprotein vaccine is a novel and promising approach for developing safe and potent nasal vaccines to combat respiratory virus infections. Full article

Rotaviruses (RVs) are non-enveloped multilayered dsRNA viruses that are major etiologic agents of diarrheal disease in humans and in the young in a large number of animal species. The viral particle is composed of three different protein layers that enclose the segmented dsRNA genome and the transcriptional complexes. Each layer defines a unique subparticle that is associated with a different phase of the replication cycle. Thus, while single- and double-layered particles are associated with the intracellular processes of selective packaging, genome replication, and transcription, the viral machinery necessary for entry is located in the third layer. This modular nature of its particle allows rotaviruses to control its replication cycle by the disassembly and assembly of its structural proteins. In this review, we examine the significant advances in structural, molecular, and cellular RV biology that have contributed during the last few years to illuminating the intricate details of the RV particle disassembly and assembly processes. Full article

SRC homology 3 (SH3) domains are fundamental modules that enable the assembly of protein complexes through physical interactions with a pool of proline-rich/noncanonical motifs from partner proteins. They are widely studied modular building blocks across all five kingdoms of life and viruses, mediating various biological processes. The SH3 domains are also implicated in the development of human diseases, such as cancer, leukemia, osteoporosis, Alzheimer’s disease, and various infections. A database search of the human proteome reveals the existence of 298 SH3 domains in 221 SH3 domain-containing proteins (SH3DCPs), ranging from 13 to 720 kilodaltons. A phylogenetic analysis of human SH3DCPs based on their multi-domain architecture seems to be the most practical way to classify them functionally, with regard to various physiological pathways. This review further summarizes the achievements made in the classification of SH3 domain functions, their binding specificity, and their significance for various diseases when exploiting SH3 protein modular interactions as drug targets. Full article

This Review initiates a wide-ranging discussion over 2023 by selecting and exploring core themes to be investigated more deeply in papers submitted to the Vaccines Special Issue on the “Future of Epidemic and Pandemic Vaccines to Serve Global Public Health Needs”. To tackle the SARS-CoV-2 pandemic, an acceleration of vaccine development across different technology platforms resulted in the emergency use authorization of multiple vaccines in less than a year. Despite this record speed, many limitations surfaced including unequal access to products and technologies, regulatory hurdles, restrictions on the flow of intellectual property needed to develop and manufacture vaccines, clinical trials challenges, development of vaccines that did not curtail or prevent transmission, unsustainable strategies for dealing with variants, and the distorted allocation of funding to favour dominant companies in affluent countries. Key to future epidemic and pandemic responses will be sustainable, global-public-health-driven vaccine development and manufacturing based on equitable access to platform technologies, decentralised and localised innovation, and multiple developers and manufacturers, especially in low- and middle-income countries (LMICs). There is talk of flexible, modular pandemic preparedness, of technology access pools based on non-exclusive global licensing agreements in exchange for fair compensation, of WHO-supported vaccine technology transfer hubs and spokes, and of the creation of vaccine prototypes ready for phase I/II trials, etc. However, all these concepts face extraordinary challenges shaped by current commercial incentives, the unwillingness of pharmaceutical companies and governments to share intellectual property and know-how, the precariousness of building capacity based solely on COVID-19 vaccines, the focus on large-scale manufacturing capacity rather than small-scale rapid-response innovation to stop outbreaks when and where they occur, and the inability of many resource-limited countries to afford next-generation vaccines for their national vaccine programmes. Once the current high subsidies are gone and interest has waned, sustaining vaccine innovation and manufacturing capability in interpandemic periods will require equitable access to vaccine innovation and manufacturing capabilities in all regions of the world based on many vaccines, not just “pandemic vaccines”. Public and philanthropic investments will need to leverage enforceable commitments to share vaccines and critical technology so that countries everywhere can establish and scale up vaccine development and manufacturing capability. This will only happen if we question all prior assumptions and learn the lessons offered by the current pandemic. We invite submissions to the special issue, which we hope will help guide the world towards a global vaccine research, development, and manufacturing ecosystem that better balances and integrates scientific, clinical trial, regulatory, and commercial interests and puts global public health needs first. Full article

Noroviruses infect a wide range of mammals and are the major cause of gastroenteritis in humans. Recombination at the junction of ORF1 encoding nonstructural proteins and ORF2 encoding major capsid protein VP1 is a well-known feature of noroviruses. Using all available complete norovirus sequences, we systematically analyzed patterns of natural recombination in the genus Norovirus both throughout the genome and across the genogroups. Recombination events between nonstructural (ORF1) and structural genomic regions (ORF2 and ORF3) were found in all analyzed genogroups of noroviruses, although recombination was most prominent between members of GII, the most common genogroup that infects humans. The half-life times of recombinant forms (clades without evidence of recombination) of human GI and GII noroviruses were 10.4 and 8.4–11.3 years, respectively. There was evidence of many recent recombination events, and most noroviruses that differed by more than 18% of nucleotide sequence were recombinant relative to each other. However, there were no distinct recombination events between viruses that differed by over 42% in ORF2/3, consistent with the absence of systematic recombination between different genogroups. The few inter-genogroup recombination events most likely occurred between ancient viruses before they diverged into contemporary genogroups. The recombination events within ORF1 or between ORF2/3 were generally rare. Thus, noroviruses routinely exchange full structural and nonstructural blocks of the genome, providing a modular evolution. Full article

The hepatitis E virus (HEV) is a long-ignored virus that has spread globally with time. It ranked $6$th among the top risk-ranking viruses with high zoonotic spillover potential; thus, considering its viral threats is a pressing priority. The molecular pathophysiology of HEV infection or the underlying cause is limited. Therefore, we incorporated an unbiased, systematic methodology to get insights into the biological heterogeneity associated with the HEV. Our study fetched $93$ and $2016$ differentially expressed genes (DEGs) from chronic HEV (CHEV) infection in kidney-transplant patients, followed by hub module selection from a weighted gene co-expression network (WGCN). Most of the hub genes identified in this study were associated with interferon (IFN) signaling pathways. Amongst the genes induced by IFNs, the 2′-5′-oligoadenylate synthase 3 (OAS3) protein was upregulated. Protein-protein interaction (PPI) modular, functional enrichment, and feed-forward loop (FFL) analyses led to the identification of two key miRNAs, i.e., miR-222-3p and miR-125b-5p, which showed a strong association with the OAS3 gene and TRAF-type zinc finger domain containing 1 (TRAFD1) transcription factor (TF) based on essential centrality measures. Further experimental studies are required to substantiate the significance of these FFL-associated genes and miRNAs with their respective functions in CHEV. To our knowledge, it is the first time that miR-222-3p has been described as a reference miRNA for use in CHEV sample analyses. In conclusion, our study has enlightened a few budding targets of HEV, which might help us understand the cellular and molecular pathways dysregulated in HEV through various factors. Thus, providing a novel insight into its pathophysiology and progression dynamics. Full article

Most plant viruses lack the 5′-cap and 3′-poly(A) structures, which are common in their host mRNAs, and are crucial for translation initiation. Thus, alternative translation initiation mechanisms were identified for viral mRNAs, one of these being controlled by an RNA element in their 3′-ends that is able to enhance mRNA cap-independent translation (3′-CITE). The 3′-CITEs are modular and transferable RNA elements. In the case of poleroviruses, the mechanism of translation initiation of their RNAs in the host cell is still unclear; thus, it was studied for one of its members, cucurbit aphid-borne yellows virus (CABYV). We determined that efficient CABYV RNA translation requires the presence of a 3′-CITE in its 3′-UTR. We showed that this 3′-CITE requires the presence of the 5′-UTR in cis for its eIF4E-independent activity. Efficient virus multiplication depended on 3′-CITE activity. In CABYV isolates belonging to the three phylogenetic groups identified so far, the 3′-CITEs differ, and recombination prediction analyses suggest that these 3′-CITEs have been acquired through recombination with an unknown donor. Since these isolates have evolved in different geographical regions, this may suggest that their respective 3′-CITEs are possibly better adapted to each region. We propose that translation of other polerovirus genomes may also be 3′-CITE-dependent. Full article

The systemic nature of COVID-19 with multiple extrapulmonary manifestations of disease, largely due to the wide tissue expression of SARS-CoV-2 major entry factors, as well as the patient-specific features of COVID-19 pathobiology, determine important directions for basic and translational research. In the current study, we addressed the questions of singularities and commonalities in cellular responses to SARS-CoV-2 and related SARS-CoV on the basis of compendium-wide analysis of publicly available transcriptomic datasets as part of the herein implemented multi-modular UNCOVIDING approach. We focused on cellular models attributed to the epithelial cells of the respiratory system, the Calu-3 cell line, and epithelial cells of the gastrointestinal tract, the Caco-2 cell line, infected with either SARS-CoV-2 or SARS-CoV. Here, we report the outcome of a comparative analysis based on differentially expressed genes in terms of perturbations and diseases, Canonical pathways, and Upstream Regulators. We furthermore performed compendium-wide analysis across more than 19,000 mRNASeq datasets and dissected the condition-specific gene signatures. Information was gained with respect to common and unique cellular responses and molecular events. We identified that in cell lines of colon or lung origin, both viruses show similarities in cellular responses; by contrast, there are cell type-specific regulators that differed for Calu-3 and Caco-2 cells. Among the major findings is the impact of the interferon system for lung Calu-3 cells and novel links to the liver- and lipid-metabolism-associated responses for colon Caco-2 cells as part of the extrapulmonary pathomechanisms in the course of COVID-19. Among differently expressed genes, we specifically dissected the expression pattern of the APOBEC family members and propose APOBEC3G as a promising intrinsic antiviral factor of the host response to SARS-CoV-2. Overall, our study provides gene expression level evidence for the cellular responses attributed to pulmonary and gastrointestinal manifestations of COVID-19. Full article