RARE DISEASE
Plague
Plague
Plague
Synonyms: Y. pestis infection, Yersinia pestis infection
Synonyms: Y. pestis infection, Yersinia pestis infection
Synonyms: Y. pestis infection, Yersinia pestis infection
Drug discovery
3
drugs
With orphan designations
Overview
Plague is a zoonotic disease caused by Yersinia pestis, transmitted through flea bites, contact with infected animals, or inhalation of respiratory droplets. It manifests as bubonic (lymphadenopathy), septicemic (systemic infection), or pneumonic (respiratory) forms, with pneumonic plague being highly contagious and fatal within 18–24 hours if untreated. Rapid diagnosis (antigen tests, culture) and early antibiotic therapy are critical, alongside strict infection control measures for pneumonic cases [1][6][18].
Burden
Case-fatality rate: 7–17% with treatment, but approaches 100% for untreated pneumonic plague [1][4][16].
Major outbreaks occur in resource-limited settings, with ~21,725 cases and 1,612 deaths reported globally from 2000–2009 [4].
Reemergence risks include antimicrobial resistance and climate-driven rodent-flea proliferation [8][18].
Categories: rare infectious diseases
Research Papers
1,025 drug discovery papers about Plague, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,025 drug discovery papers about Plague, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
vaccines
2026-07-22 | Live attenuated vaccines alone or in combination with an adenovirus-based vaccine protect mice lacking IFN-γ against pneumonic plague.
Two live-attenuated vaccines, LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their protective efficacy against pneumonic plague in wild-type (WT) and interferon-γ (IFN-γ) knockout (KO) mice. LMA and LMP comprise triple deletion mutants of Yersinia pestis CO92, which causes pneumonic plague, and Ad5-YFV incorporates three protective plague immunogens. Protection of 80 to 100% was observed in vaccinated mice when challenged with highly lethal intranasal doses of parental Y. pestis CO92. All vaccinated mice generated robust humoral and cellular immune responses. Immunized WT mice generated overall greater antibody responses in both serum and bronchoalveolar lavage fluid with higher percentages of polyfunctional T cell populations. Vaccinated IFN-γ KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen-specific and memory T cells. Superior lung immunity and recall immune responses were observed in both WT and IFN-γ KO mice immunized using a prime-pull vaccine strategy, which also provided full protection against pneumonic plague to mice lacking IFN-α, IFN-β, and IFN-γ receptors. Depletion of IFN-γ or tumor necrosis factor-α from immunized WT mice before and during infection did not reduce protection against pulmonary Y. pestis CO92 challenge. These data suggest that IFN-γ may not be required for protection against pneumonic plague by these vaccines. Combining live-attenuated and adenovirus-based vaccines resulted in augmentation of systemic and local immune responses, which could be beneficial in providing long-lasting immunity against pneumonic plague.
2026-02-25 | An adenoviral-vectored vaccine protects mice against aerosol challenge with Yersinia pestis.
With the success of viral-vectored vaccines against Ebola and SARS-CoV-2, these platforms are now established as promising tools for biodefence against outbreak pathogens. Here, we report the development of adenoviral-vectored vaccines against plague, caused by Yersinia pestis. Replication-deficient adenoviral-vectored constructs expressing the protective Y. pestis antigens F1 and LcrV, alone or in combi and combinations thereof were created. Expression of the antigens was confirmed in vitro, and immunogenicity assessed in mice. Protective efficacy was evaluated using a virulent Y. pestis aerosol challenge model in mice. All vaccine candidates induced high serum IgG antibody responses. Notably, the antibody responses were similar when vectors expressing different antigens were mixed or when using a single vector expressing a chimeric fusion of the two antigens. All of the six experimental vaccine formulations tested via intramuscular injection containing either the V gene or purified V protein provided 90%-100% protection from mortality due to inhalational infection with Y. pestis. Notably, only the human adenovirus 5 construct expressing a full length F1-V fusion provided 100% protection from both morbidity and mortality after a single dose. In contrast, naive mice and 50% of mice immunized with two doses of the recombinant proteins with adjuvant displayed clinical signs of illness (morbidity) despite protection from mortality. Importantly, in a follow-up virulent aerosol challenge study, a single dose of ChAdOx1 F1-V fusion provided protection comparable to that achieved with HuAd5 vaccine. Based on these results, a ChAdOx1 F1-V fusion vaccine has progressed to phase I human clinical trials.
2026-01-28 | Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing.
Yersinia pestis caused the three plague pandemics that claimed more than two hundred million human lives. There is still no vaccine that meets all WHO requirements, and many researchers continue to develop plague vaccines using various technological platforms. For example, researchers led by Roy Curtiss 3rd have developed a new approach to achieve controlled, delayed attenuation of bacterial pathogens. Mutants generated using this method were superior in protecting Y. pestis-infected mice immunized with strains generated using traditional gene knockout. However, further studies are needed to determine the safety and efficacy of these delayed-attenuated strains in other mammalian species in order to extrapolate on humans the data obtained in accordance with the FDA Animal Rule. Three Y. pestis strains, a Δcrp mutant, a mutant with arabinose-dependent regulated crp expression (araC PBADcrp) or an araC PBADcrp mutant cured of plasmid pPst were derived from virulent wild-type strain 231. To evaluate the safety, outbred mice or guinea pigs were immunized subcutaneously with serial tenfold dilutions of mutated strains. For vaccine studies, immunized animals were subcutaneously challenged with 200 LD100 (lethal dose in all exposed subjects) of the wild-type Y. pestis strain. The challenge caused the death of 100% of naïve animals in controls. The Y. pestis strain 231Δcrp was nonlethal in mice at a dose of 107 CFs. The LD50 of the 231Δcrp strain in guinea pigs increased by at least 107-fold compared to that of the wild-type strain. The LD50s of the 231PBAD-crp mutant in mice and guinea pigs were approximately 104-fold and 107-fold higher than those of Y. pestis 231, respectively. The 231PBAD-crp(pPst¯) strain did not cause death in mice (LD50 > 107 CFU) and guinea pigs (LD50 > 109 CFU) when administered subcutaneously and was capable of inducing intense protective immunity in both species of laboratory animals. Our research has shown once again the necessity of balance between safety and effectiveness demonstrating the feasibility of further investigation of crp mutants as promising candidate plague vaccines.
2026-01-14 | Intranasal unadjuvanted LcrV boosts parental Yersinia OMV primed lung immunity against pneumonic plague in mice.
Pneumonic plague remains a high-consequence respiratory disease, highlighting the need for vaccines that induce durable lung-localized immunity. We show that intramuscular prime-boost vaccination with Alum-absorbed OMV46-LcrV (OMV46-LcrV/Alum) is safe but provides limited long-term protection against respiratory Yersinia pestis challenge in mice. To enhance lung immunity, we deliver an adjuvant-free intranasal LcrV "spike" following IM OMV46-LcrV/Alum priming. This "prime-spike" regimen is well tolerated and confers complete short- and long-term protection against high-dose pulmonary Y. pestis challenge. The approach increases lung resident memory B cells, including antibody-secreting cells, and resident memory T cells with elevated Interferon-γ, Interleukin-17A, and Interleukin-4 production. These localized memory responses contribute to improved protection, demonstrating the promising potential of prime-spike immunization for combating pneumonic plague.
2025-09-20 | Lipid A mimetic BECC438 potentiates durable and balanced antibody responses in an ovalbumin murine model of vaccination.
The need for effective infectious disease vaccines has become an inescapable topic in recent years. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include adjuvants that avoid excessive adverse reactions while allowing for dose and antigen sparing. Bacterially derived TLR4 agonist, BECC438, has recently emerged as a lead adjuvant candidate across several experimental models of infectious disease, including Yersinia pestis (plague), human papillomavirus, influenza A (flu), SARS-CoV-2 (COVID-19), and Shigella spp (gastrointestinal infection). To confirm that BECC438 is a high-quality immunoadjuvant, even without antigen from an infectious pathogen, studies presented here use the model antigen ovalbumin in a murine prime-boost vaccine model. Durable and more balanced production of antibody isotypes IgG1 and IgG2 is observed when the bacterial enzyme combinatorial chemistry adjuvant is used, as compared with the classic adjuvants aluminum salts (Alhydrogel) and synthetic monophosphorylated lipid A-PHAD (phosphorylated hexaacyl disaccharide). Antibody responses are maintained for at least 18 wk postvaccination. Observed immune metrics maintained similar trends across males, females, and genetic backgrounds, including C57BL/6, BALB/c, and CD-1 (outbred) mice, with males overall showing a lower production of IgG2c. In vitro analysis of C57BL/6 serum showed an increased half-life of ovalbumin-specific antibodies in BECC438 adjuvanted animals, indicative of a higher antigen binding affinity. These studies provide continued evidence to support the development of the BECC438 adjuvant in vaccines for human use.
proteins
2026-06-17 | Spatiotemporal dynamics of the capture rate of Rattus tanezumi and its implications for rodent-borne diseases in the Three Gorges Reservoir Area, China.
Rattus tanezumi (R. tanezumi) is a major amplifying host for plague and an important reservoir host for multiple zoonotic pathogens, including leptospirosis and hantavirus. Its population dynamics in the Three Gorges Reservoir (TGR) Area of China are influenced by climate and reservoir-induced environmental changes, thereby impacting disease transmission risks. Based on rodent capture rate data collected using cage traps during night surveys in January, March, May, July, September, and November each year from 2015 to 2021, this study investigated the spatiotemporal dynamics of R. tanezumi and its association with key meteorological and environmental factors. Using Geographic Information Systems (GIS) for spatiotemporal analysis and a Generalized Additive Model (GAM), we identified the current month's average temperature and relative humidity, together with 3-month-lagged precipitation and the Normalized Difference Vegetation Index (NDVI), as associated factors. The highest capture rate occurring at around 20 °C. Rat capture rate negatively correlated with both current relative humidity and lagged precipitation and a fluctuating decline with increasing lagged NDVI. This study demonstrates how climatic and environmental factors shape the spatiotemporal distribution of R. tanezumi population in the Three Gorges Reservoir Area. These findings provide insights that may inform predictions of rodent‑borne disease risks and support the development of targeted surveillance and control strategies in this ecologically vulnerable region.
2026-05-13 | Evolutionary trends of plague research from 2016 to 2025: A bibliometric analysis.
Plague is a severe zoonotic disease caused by Yersinia pestis, a pathogen characterized by high infectivity and mortality rates. Historically, three global pandemics have inflicted heavy disasters on human society. Despite improvements in control measures and the application of antibiotics, plague has been somewhat controlled; however, since the beginning of the 21st century, plague outbreaks have continued to occur in regions with a high burden of neglected tropical diseases (NTDs) in Africa, the Americas, and Asia. In recent years, the rapid development of technologies such as molecular biology, immunology, and bioinformatics has propelled significant advancements in plague diagnostics, vaccine development, and transmission mechanisms. However, there has been a lack of systematic quantitative analysis of the distribution characteristics, evolving hotspots, and frontier trends of plague research, which makes it challenging to provide comprehensive scientific support for research and control decision-making. Search for relevant literatures on plague that were published in the Web of Science Core Collection and PubMed database from January 1, 2016 to November 12, 2025.Bibliometric methods were adopted, and software including COOC 20.6, VOSviewer 1.6.20, and Anaconda were used to analyze the publication trend, distribution of institutions, national cooperation network, keyword co-occurrence clustering, and the annual variation trends. A total of 1994 documents were finally included. The annual number of publications showed an overall fluctuating upward trend, with a significant growth rate from 2020 to 2021 (annual growth rate of 10.44%). Core research institutions included the U. S. Centers for Disease Control and Prevention and Beijing Institute of Microbiology and Epidemiology. The United States, China, France and Madagascar were the main core countries for cooperation. Keyword co-occurrence clustering identified five major research fields, which were plague vaccine development and immune mechanism, ecology and vector control, historical epidemiology and public health, epidemiology and transmission chain, and plague-related infectious diseases and biosafety. The research trends analysis showed that from 2016 to 2020, the plague research mainly focused on keywords such as "Rodents" "Epidemiological Survey" "Human Plague" and "Fleas". From 2021 to 2025, "Phylogenetic Analysis," "Public Health," and "Madagascar" newly entered the top 20 keyword list; the frequencies of "Black Death" and "Infectious Disease" increased significantly, while the frequencies of "Plague Vaccine" and "Prairie Dogs" remained relatively stable. Over the past decade, remarkable achievements have been made in plague research. Interdisciplinary integration and technological innovation have continued to deepen. However, global collaboration remains insufficiently developed. In the future, it is necessary to foster broader cross-regional cooperation, accelerate the research, development and translation of vaccines and diagnostic technologies, integrate multiple technologies to construct a precise prevention and control system. and enhance the global collaborative prevention and control capabilities of plague.
2026-03-07 | Application of Long-Read Sequencing for Genotyping, Epigenetic Profiling and Surveillance of Yersinia pestis Isolates from Natural Foci and Disease Outbreaks in Central Asia.
This study explores the application of long-read sequencing technologies for genotyping, epigenetic profiling, and epidemiological monitoring of Yersinia pestis isolates obtained from natural foci in Central Asia and previous zoonotic outbreaks. Computational tools for genome assembly and genotyping were developed, enabling high-precision identification of both chromosomal and plasmid sequences, including the small plasmid pCKF. Genotyping based on genetic polymorphisms distinguished the major Y. pestis biovars and lineages, and revealed cluster-specific diversity among Medievalis (2.MED) isolates, including groups of strains associated with different plague foci and disease outbreaks in domestic animals and humans. These specific genomic polymorphisms identified in subclades of 2.MED isolates allow their high-precision identification. The distribution of pCKF-positive strains in the region and the potential involvement of these pathogens in disease outbreaks are discussed. Additionally, comparative epigenomic analysis uncovered strain-specific cytosine methylation patterns at cgGATCG motifs. Further studies involving more sequenced strains are needed to determine whether this cytosine methylation specificity is linked to genome function regulation and adaptation to different hosts and environments. These findings demonstrate the effectiveness of long-read sequencing technologies in revealing both genetic and epigenetic features of bacterial pathogens, contributing to our understanding of the evolutionary mechanisms underlying the emergence and spread of this especially dangerous infection.
2026-01-22 | Imperial Careering: India and the Women's Medical Movement, 1896-1920.
India figured prominently in the women's medical movement of the late nineteenth and early twentieth centuries. It was both a cause-bringing medical aid to Indian women-and a career-offering employment opportunities to qualified British women doctors. Where most studies have focussed on the early years of the movement in India and the creation of the Dufferin Fund in 1885, this article explores the careers, attitudes and experiences of a second generation of white women doctors, from the outbreak of bubonic plague in 1896 to the end of the First World War. As an exercise in imperial careering, it charts the parallels and connections between women doctors in India and Britain but also assesses the obstacles to the pursuit of medical careers in India and the factors, personal, political and professional, that by 1920 were driving women's medicine in metropole and empire further apart.
2026-01-16 | Commentary on Seersholm Et al.: Yersinia pestis Infection Is Not Synonymous With Deadly Plague in Neolithic Scandinavia.
Emerging genomic evidence has identified ancestral strains of Yersinia pestis in ancient human populations, which has sparked debates about its pathogenic role in later Neolithic societies. Here, we review published evidence linking anthropological and biological data reflecting the past natural history of Y. pestis infection. Review of reported ancient Y. pestis genomes, paleomicrobiological, archaeological, and ecological data related to ancient plague. While some researchers attributed the Scandinavian Neolithic population decline to plague epidemics, we argue that early Y. pestis strains were more likely associated with outbreaks of food-borne enteritis rather than flea-borne plague. This hypothesis is supported by genetic, archaeological, and ecological analyses, which indicate that Y. pestis evolved key flea-borne transmission mechanisms only later in its history.
small molecules
2026-08-17 | The 1820 Mallorca plague was not a classic bubonic outbreak.
The 1820 plague outbreak in eastern Mallorca-long treated as a local episode and traditionally classified as a late bubonic manifestation of the Second Plague Pandemic-offers a unique opportunity to reassess transmission dynamics in a prebacteriological context. Using a previously unexamined primary source consisting of daily counts of deaths, we combine historical analysis with a Bayesian epidemiological model to estimate the basic reproduction number ([Formula: see text]), the mean infectious period, and the case-fatality ratio in the towns of Son Servera and Capdepera (Mallorca, Spain). Our results show stark contrasts between the two towns: Son Servera exhibited a higher transmission potential ([Formula: see text]) and longer infectious period ([Formula: see text]2.8 d) than Capdepera ([Formula: see text]; [Formula: see text]2.0 d). The overall case-fatality rate of 78%-together with short infectious periods and historical descriptions of rapid clinical decline-strongly suggests that pneumonic and septicemic forms contributed substantially to transmission, challenging earlier interpretations centered on bubonic plague and rodent-borne spread. Historical evidence also rules out an enzootic rat reservoir, pointing instead to human ectoparasites or direct human-to-human routes as the most likely drivers. Moreover, mortality among children increased significantly during the outbreak, indicating age-differentiated vulnerability. By integrating quantitative modeling with fine-grained archival records, this study reassesses the biological nature of one of the last major plagues in 19th-century western Europe and contributes to broader debates on plague ecology, transmission mechanisms, and the dynamics of late Second Pandemic outbreaks.
2026-05-13 | Fipronil Baits as Emerging Tools for Flea Control and Plague Mitigation: Experiments with Cricetid Mice on Prairie Dog Colonies.
Plague is a zoonotic disease of mammalian hosts and flea vectors. Wildlife biologists most commonly mitigate plague by controlling flea populations. We evaluated the efficacy of edible baits for systemic flea control with two cricetid species on colonies of black-tailed prairie dogs (Cynomys ludovicianus): the western deer mouse (Peromyscus sonoriensis) and the northern grasshopper mouse (Onychomys leucogaster). We tested grain bait with 0.005% fipronil by weight and "FipBit" pellets with 0.46-1.52 mg of fipronil/pellet. Flea prevalence was assessed via combing of live-trapped mice. In one experiment with fipronil grain bait and FipBits (n=564 combings), flea prevalence declined from 74% (grain) and 45% (FipBits) before treatments to 0% for both treatments from 30-44 d and from 324-413 d after treatments. During a second experiment with FipBits (n=299 combings), flea prevalence declined from 13% to 32% before treatments to 0% from 11-15 d after treatments, but increased to 29-56% from 349-378 d after treatments. Results herein suggest annual fipronil bait treatments may be most effective for flea control.
2026-03-26 | Edible baits for systemic flea control, plague mitigation, and wildlife conservation: evaluation of four active ingredients with three rodent species in western North America.
The flea-borne agent of plague, Yersinia pestis, is lethal to endangered black-footed ferrets (Mustela nigripes, BFFs) and the prairie dogs (Cynomys spp., PDs) on which BFFs depend for habitat and prey. We developed bait pellets containing insecticides for flea control with PDs. Individual baits contained 0.46, 0.91, 1.21, or 1.52 mg fipronil, 5.40 mg afoxolaner, 50.62 mg fluralaner, or 85.20 mg spinosad. From 2023 to 2025, we tested the baits with black-tailed PDs (C. ludovicianus, BTPDs), Gunnison's PDs (C. gunnisoni, GPDs), and Richardson's ground squirrels (Urocitellus richardsonii, RGSs). We sampled hosts 2810 times and detected 8825 fleas across 2 U.S. States, 1 Canadian Province, 6 sites, 9 PD colonies, and 41 sampling plots. Over ∼12 mo across 5 replicates in South Dakota, USA, bait pellets with 0.91 or 1.52 mg fipronil, applied at a rate of 125 baits/ha, were more effective in reducing the abundance of fleas on BTPDs than 0.46 mg fipronil or the 3 other active ingredients; on 2 South Dakota replicates with data from 24 mo posttreatment, the effects of fipronil pellets on flea abundance had waned after ∼24 mo. Similarly, over ∼12 mo on 2 replicates in Arizona, USA, pellets with 1.52 mg fipronil were more effective in reducing the abundance of fleas on GPDs than pellets with 0.46 mg fipronil; on 1 replicate with available data from ∼2 yr posttreatment, the effects of fipronil pellets had waned after ∼24 mo. Over ∼8-11 mo across 2 replicates in Saskatchewan, Canada, baits with 1.21 mg fipronil/pellet were more effective in suppressing the abundance of fleas on BTPDs and RGSs when applied at 250 pellets/ha than 62 pellets/ha; flea control had waned after ∼20-23 mo. When applied annually at 125-250/ha, baits with 0.84-1.52 mg fipronil (FipBits) provided an effective, efficient, and affordable tool for flea control on PD colonies.
2026-03-01 | PLAGUE IN THE 21ST CENTURY: GLOBAL OVERVIEW AND PERSPECTIVES IN BRAZIL
Yersinia pestis , the causative agent of plague, evolved from Y. pseudotuberculosis about 6,000 years ago and remains a relevant zoonotic pathogen in the 21st century. Although associated with major historical pandemics, a significant number of human cases are still reported annually, resulting in hundreds of deaths from its most notable forms, bubonic and pneumonic. Knowledge of the epidemiology of this infection is therefore essential for healthcare professionals in the differential diagnosis of febrile syndromes. To estimate the current prevalence of human Y. pestis infections and to evaluate plague case fatality rates in its most common forms. A literature review was conducted exclusively in the PubMed/PMC database, including epidemiological studies, case series, and surveillance analyses published between 1990 and 2023. Articles presenting quantitative data on human cases, regional distribution, and case fatality rates were selected. Between 2000 and 2010, 21,725 plague cases and 1,612 deaths were reported globally, resulting in an approximate case fatality rate of 7.4%. In the United States, from 1900 to 2012, 1,006 cases were recorded, with a recent average of seven cases per year, mainly concentrated in the western states. In Brazil, active bubonic plague foci persisted until the 1960s, totaling more than 2,000 documented cases between 1936 and 1956. Studies identified continued presence of Yersinia pestis in rodents and fleas in the Northeast until 2005, maintaining potential risk of reemergence, although no recent human cases have been reported. Entomological and animal surveillance remains active in these regions. Regarding severity, the case fatality rate for treated bubonic plague is around 8–10%, while for pneumonic plague, without rapid intervention, it can exceed 50%. These data reinforce that although plague is currently rare, it remains a relevant zoonosis, especially in areas with confirmed circulation of Yersinia pestis in wild reservoirs. The high lethality of pneumonic forms and persistence of natural foci, as historically observed in Brazil and still present in other regions worldwide, make the maintenance of continuous epidemiological surveillance, environmental monitoring, and rapid response strategies indispensable to prevent reemergence.
2026-01-20 | Structural and Biophysical Characterization of the Yersinia Type Three Secretion System ATPase YscN.
Yersinia pestis was responsible for the Black Plague, one of the worst epidemiological disasters in recorded history. Today, Y. pestis , Y. enterocolitica , and Y. pseudotuberculosis remain clinically relevant human pathogens. Each of these pathogenic Yersinia species relies on a Type Three Secretion System (T3SS) for virulence, with the ATPase YscN playing a critical role in T3SS function. T3SS ATPases are responsible for powering apparatus formation and effector protein secretion through ATP hydrolysis. This study provides an extensive enzymatic characterization of recombinant YscN under several conditions, including variable pH and temperature, substrate and protein concentrations, and in the presence of putative inhibitors. Thermal stability data, assessed by circular dichroism, demonstrate that YscN exhibits increased stability in alkaline conditions, coinciding with greatest ATPase activity. Further, we report the first high-resolution crystal structure of YscN and leverage homology data to model an oligomeric active site. Mutational analysis of a predicted active site residue confirms oligomerization as necessary for YscN ATPase activity and corroborates our oligomeric model and enzyme concentration-dependent specific activity. Interestingly, however, AUC analysis reveals that the purified YscN predominantly exists as a monomer, despite oligomerization-dependent active site formation. Thus, we propose that transient oligomeric interactions support the observed ATP hydrolysis. Together, these data uncover structural and environmental impacts on YscN activity that may support the highly specialized Yersinia pathogenic lifecycle and leverage its role in virulence in search of pan-effective small molecule T3SS ATPase inhibitors.
antibodies
2026-07-08 | Protective outcomes of high-affinity monoclonal antibodies against drug-resistant plague strains.
Yersinia pestis, a category A infectious organism, is known to cause bubonic, septicemic, and pneumonic plague. With the emergence of streptomycin-resistant strains, there is an urgent need for new therapeutic strategies that can protect populations from Y. pestis infection. The main strategy for developing vaccines and therapeutic antibodies involves F1 antigen. Previous research has demonstrated that both human and murine monoclonal antibodies(mAbs) confer protective effects against Y. pestis infection. While, no relevant studies were identified on mAbs against drug-resistance Y. pestis. Here, we constructed an antibody library from Y. pestis vaccine strain EV76-immunized mice by phage display. The mAbs were baited by recombinant F1 antigen, and the biological functions of the obtained mAbs were assessed and evaluated in plague-challenged mice. For the Y. pestis strain 141 group, both Fm3 and Fm25 provided 100% protection at a dose of 100 µg. At 20 µg, only Fm3 conferred partial protection, with a survival rate of 25%, whereas all mice in the 4 µg treatment groups succumbed to infection within approximately 10 days. Against the drug-resistant Y. pestis strain S19960127, Fm25 at 100 µg resulted in complete survival, whereas Fm3 at the same dose conferred 75% protection. Neither mAbs showed protective efficacy at 20 µg or 4 µg, and all animals dying within approximately 10 days post-infection. These findings indicated that mAbs Fm3 and Fm25 confer protection against virulent and drug-resistant strains of Y. pestis.
2026-06-23 | Table 1_Protective outcomes of high-affinity monoclonal antibodies against drug-resistant plague strains.doc
Background Yersinia pestis, a category A infectious organism, is known to cause bubonic, septicemic, and pneumonic plague. With the emergence of streptomycin-resistant strains, there is an urgent need for new therapeutic strategies that can protect populations from Y. pestis infection. The main strategy for developing vaccines and therapeutic antibodies involves F1 antigen. Previous research has demonstrated that both human and murine monoclonal antibodies(mAbs) confer protective effects against Y. pestis infection. While, no relevant studies were identified on mAbs against drug-resistance Y. pestis. Methods Here, we constructed an antibody library from Y. pestis vaccine strain EV76-immunized mice by phage display. The mAbs were baited by recombinant F1 antigen, and the biological functions of the obtained mAbs were assessed and evaluated in plague-challenged mice. Results For the Y. pestis strain 141 group, both Fm3 and Fm25 provided 100% protection at a dose of 100 µg. At 20 µg, only Fm3 conferred partial protection, with a survival rate of 25%, whereas all mice in the 4 µg treatment groups succumbed to infection within approximately 10 days. Against the drug-resistant Y. pestis strain S19960127, Fm25 at 100 µg resulted in complete survival, whereas Fm3 at the same dose conferred 75% protection. Neither mAbs showed protective efficacy at 20 µg or 4 µg, and all animals dying within approximately 10 days post-infection. Conclusion These findings indicated that mAbs Fm3 and Fm25 confer protection against virulent and drug-resistant strains of Y. pestis.
2026-02-23 | Pulmonary delivery of a humanized heavy-chain antibody LcrV-X19-R1 confers complete protection against fatal pneumonic plague in mice.
Pneumonic plague is the most fatal form of plague, with a mortality rate approaching 100% within 24 h if untreated. The emergence of drug-resistant Yersinia pestis strains capable of human-to-human transmission poses a significant challenge to conventional antibiotic therapies. While therapeutic antibodies present a promising alternative, their intravenous administration is limited by low pulmonary bioavailability and suboptimal efficacy. Targeting LcrV, a key virulence factor of Yersinia pestis type III secretion system, we developed a humanized heavy-chain antibody designated LcrV-X19-R1, and formulated it for inhalation delivery. LcrV-X19-R1 exhibited a high affinity for LcrV (KD of 0.561 nM), demonstrated good thermal stability, produced inhalable aerosol particles with a mass median aerodynamic diameter of ≤5 μm after nebulization, and showed a favorable safety profile in vivo, with all these properties meeting the criteria for effective pulmonary deposition. In a lethal mouse model of pneumonic plague, pulmonary delivery of LcrV-X19-R1 achieved 100% survival, completely cleared the bacterial loads in organs, and markedly reduced tissue damage. The protective mechanism of LcrV-X19-R1 involves direct bacterial neutralization in tissues and enhanced clearance via antibody-dependent cellular phagocytosis, which together dampen harmful inflammation and promote tissue repair. Pharmacokinetically, pulmonary delivery achieved roughly 10-fold higher lung antibody levels and retention beyond 120 h, far surpassing intravenous administration. These advantages ultimately translated into a 70% survival rate, compared to 0% with intravenous treatment. This study establishes a mucosal therapeutic strategy against pneumonic plague and provides a versatile platform for developing antibody-based interventions against other respiratory infectious diseases.
2024-12-16 | Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis.
Yersinia pestis is the gram-negative bacterium responsible for plague, one of the deadliest and most feared diseases in human history. This bacterium is known to infect phagocytic cells, such as dendritic cells and macrophages, but interactions with non-phagocytic cells of the adaptive immune system are frequently overlooked despite the importance they likely hold for human infection. To discover human genetic determinants of Y. pestis infection, we utilized nearly a thousand genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study method called Hi-HOST (High-throughput Human in-vitrO Susceptibility Testing). We identified a nonsynonymous SNP, rs2282284, in Fc receptor like 3 (FCRL3) associated with bacterial invasion of host cells (p=9×10-8). FCRL3 belongs to the immunoglobulin superfamily and is primarily expressed in lymphocytes. rs2282284 is within a tyrosine-based signaling motif, causing an asparagine-to-serine mutation (N721S) in the most common FCRL3 isoform. Overexpression of FCRL3 facilitated attachment and invasion of non-opsonized Y. pestis. Additionally, FCRL3 colocalized with Y. pestis at sites of cellular attachment, suggesting FCRL3 is a receptor for Y. pestis. These properties were variably conserved across the FCRL family, revealing molecular requirements of attachment and invasion, including an Ig-like C2 domain and a SYK interaction motif. Direct binding was confirmed with purified FCRL5 extracellular domain. Following attachment, invasion of Y. pestis was dependent on SYK and decreased with the N721S mutation. Unexpectedly, this same variant is associated with risk of chronic hepatitis C virus infection in BioBank Japan. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.
2024-11-22 | From the ports to the hinterland. Plague, bacteriology, and politics in Argentina (1899-1940).
In 1899, the first cases of plague were recognised in Paraguay and a few months later in Buenos Aires as part of the third plague pandemic. In the first decades of the twentieth century, plague slowly advanced towards the Argentinian hinterland. In this paper we focus on the production of scientific knowledge about plague in Argentina, where a core of bacteriologists emerged early on. We show how they not only played a central role in the complex process of plague recognition and intervention, but also influenced the scientific development of bacteriology in Argentina and potentially in South America. We argue that bacteriology became a key tool in articulating the promises of modern science with political and economic interests, allowing the Argentinian government to extend its territorial control over Buenos Aires and the hinterland. This can be seen in two different configurations of the plague as an epistemic and political object in Argentina. In the first period, from 1899 to 1910, plague was a problem linked to the ports. In this section of the article, we show how plague became an important issue in the development of bacteriology in Argentina, how this research contributed to new intervention measures and, in some cases, developed innovative ideas about serotherapeutic treatments and the characteristics of the disease. In the second period, from the mid-1910s until the 1940s, research in Argentina provided new evidence of the 'rural' nature of plague, a process in deep dialogue with research on plague among peri-domestic and wild rodents carried out in other parts of the Americas, Europe and Africa. This article thus aims to contribute to a history of bacteriology that highlights the role of non-European centres, like Argentina, in the production and circulation of bacteriological knowledge.
other
2026-05-13 | Targeting Undruggable Protein Interactions with DNA Aptamers: Inhibition of the Interaction Between Yersinia Outer Protein M and Human DEAD-Box Helicase 3.
The plague, caused by Yersinia pestis, has resulted in significant mortality over the past century. Despite advances in antimicrobial therapy, plague remains a re-emerging infectious disease with ongoing outbreaks and increasing concerns regarding antimicrobial resistance. Today, plague cases are still being reported, and the loss of effectiveness of treatment methods remains a major challenge. Therefore, effective treatment strategies are needed. In this study, we aimed to develop aptamers specific to Yersinia outer protein M (YopM), a key immunosuppressive protein that is essential for virulence. Our goal was to develop an aptamer that binds to YopM and inhibits its interaction with the human DEAD-box helicase 3 (DDX3) protein. YopM-DDX3 protein interaction was targeted because of its key role in nucleocytoplasmic shuttling of YopM. To achieve this, we developed the YopM16 aptamer using magnetic bead-based (Systematic Evolution of Ligands by Exponential Enrichment) (SELEX). The selected YopM16 aptamer exhibited a half-maximal inhibitory concentration(IC50) value of 103.3 ± 2 nM and effectively inhibited the interaction between YopM and DDX3. The inhibitory effect of the aptamer on protein interaction was confirmed using a pull-down assay and colorimetric test. Given that protein-protein interaction surfaces are considered undruggable, YopM16 is a promising inhibitor with the potential to serve as a molecular tool to investigate the virulence mechanism of YopM, as well as a novel antibacterial agent upon validation of its inhibition in cellular models.
2026-01-23 | Inhalable DNA nano-adjuvant elicits robust lung-resident memory immunity against pneumonic plague.
Pneumonic plague, caused by Yersinia pestis, remains a deadly threat due to its high mortality and rapid progression. In our previous study, Yersinia pestis antigens formulated with CpG oligodeoxynucleotides show great potential against pneumonic plague, but these agonists display low TLR9 affinity, poor stability, limited cellular uptake, and weak induction of tissue-resident memory immunity. Here, we introduce AdjCRU, a cruciform DNA nano-adjuvant built on a four-way junction with each arm presenting looped CpG motifs (LoDNA) for TLR9 engagement. Guided by computational design and molecular dynamics simulations, the four-way junction is chosen over other nanostructures for superior TLR9 binding. AdjCRU is nuclease-resistant, prepared by one-step annealing of four single-stranded oligonucleotides. When administered via aerosolized intratracheal inoculation alongside Yersinia pestis recombinant antigen rV10, AdjCRU is effectively internalized into lysosomes of antigen-presenting cell (APC), inducing markedly enhanced APC maturation, germinal center reaction, systemic and mucosal antibody titers, and T/B cell activation. Notably, rV10+AdjCRU drives robust lung-resident memory T/B cell immunity, and significantly improves survival by 40 % over free LoDNA in a lethal pneumonic plague mouse model. By integrating programmability, biocompatibility, and enhanced TLR9 stimulation into a single, modular platform, AdjCRU offers a versatile strategy for next-generation mucosal adjuvants against respiratory pathogens.
2025-10-29 | Plagued by the Past, Pressed by the Present: A One Health Perspective on Yersinia pestis.
Yersinia pestis, the causative agent of plague, is arguably the most devastating pathogen in human history. Paleogenomic studies indicate its presence as early as the Neolithic era. It evolved from Yersinia pseudotuberculosis, with divergence estimates ranging from 1500 to 20,000 years ago, most often placed around 5000 years ago. Its natural reservoirs are wild mammals, particularly rodents, with fleas serving as vectors, while humans are incidental hosts. Over time, Y. pestis has acquired multiple virulence factors that disrupt immune responses and can lead to rapid, often fatal disease. Because the bacterium is maintained in wildlife cycles and can spill over to domestic animals, eradication is difficult, if not impossible. Nevertheless, mitigation is achievable using a One Health approach integrating human health, animal health, and the health of the environment. Neither vaccines nor monoclonal antibodies are currently licensed in most Western countries, thus, antibiotics remain the mainstay of therapy. Timely administration, ideally within 24 h of symptom onset, is critical, particularly in pneumonic forms. Phage therapy is under investigation as a potential treatment. Though often neglected in high-income settings, plague remains endemic in several regions, with the highest burden reported in Madagascar and the Democratic Republic of the Congo.
2025-07-09 | Rapid adaptation to a globally introduced virulent pathogen in a keystone species.
Emerging infectious diseases are one of the foremost contemporary threats to biodiversity conservation. Outbreaks of novel pathogens can lead to the extinction of host populations, loss of gene flow due to extirpation, and bottlenecks in host populations with surviving individuals. In outbreaks with survivors, pathogens can exert strong selection on hosts, in some cases leading to the evolution of resistance or tolerance in the host population. The pathogen causing sylvatic plague, Yersinia pestis, was introduced to North America in the early 1900s and caused widespread population declines in prairie dogs (genus Cynomys), which experience >95% mortality during epizootics. Recently, survival from plague was documented in a small number of black-tailed prairie dogs (Cynomys ludovicianus) in natural populations in Colorado (United States). We performed whole-genome sequencing on all seven individuals that survived infection with plague and seven individuals that likely died. Using genome-wide association tests, F ST outlier tests, and other inferences of selection, we detected single nucleotide polymorphisms (SNPs) on five scaffolds that were strongly associated with survivorship from plague in nature. One candidate gene, inducible T-cell stimulator (ICOS), was also associated with survival in humans during the Black Death in London (United Kingdom), suggesting conservation of gene function across taxonomically diverse lineages. In addition, three candidate genes (TMEM198, PCDHB12/15, and KIAA1191) are different from but in the same gene classes (transmembrane proteins, protocadherins, and Kasuza protein-binding genes) as candidate genes for plague resistance in great gerbils, providing support for the hypothesis that parallel evolution may occur at the level of gene classes in addition to individual genes. Understanding the genomic basis of immunity can enable genetically informed management actions, such as targeted relocation to protect grassland species. Moreover, understanding how rapid adaptation to pathogens occurs can help us predict the time frame and spatial scale at which adaptation may occur, during which other interventions are needed.
2025-05-29 | Attenuation of virulence in Yersinia pestis across three plague pandemics.
Yersinia pestis has spilled over from wild rodent reservoirs to commensal rodents and humans, causing three historically recorded pandemics. Depletion in the copy number of the plasmid-encoded virulence gene pla occurred in later-dated strains of the first and second pandemics, yet the biological relevance of the pla deletion has been difficult to test. We identified modern Y. pestis strains that independently acquired the same pla depletion as ancient strains and herein show that excision of pla from the multicopy pPCP1 plasmid is accompanied by the integration of a separate full pPCP1 harboring pla into the single-copy pCD1 plasmid, reducing pla dosage. Moreover, we demonstrate that this depletion decreases the mortality of mice in models of bubonic plague but not in the pneumonic and septicemic forms of the disease. We hypothesize that pla depletion may have been selectively advantageous in bubonic plague, owing to rodent fragmentation after pandemic-induced mortality.
vaccines
2026-07-22 | Live attenuated vaccines alone or in combination with an adenovirus-based vaccine protect mice lacking IFN-γ against pneumonic plague.
Two live-attenuated vaccines, LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their protective efficacy against pneumonic plague in wild-type (WT) and interferon-γ (IFN-γ) knockout (KO) mice. LMA and LMP comprise triple deletion mutants of Yersinia pestis CO92, which causes pneumonic plague, and Ad5-YFV incorporates three protective plague immunogens. Protection of 80 to 100% was observed in vaccinated mice when challenged with highly lethal intranasal doses of parental Y. pestis CO92. All vaccinated mice generated robust humoral and cellular immune responses. Immunized WT mice generated overall greater antibody responses in both serum and bronchoalveolar lavage fluid with higher percentages of polyfunctional T cell populations. Vaccinated IFN-γ KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen-specific and memory T cells. Superior lung immunity and recall immune responses were observed in both WT and IFN-γ KO mice immunized using a prime-pull vaccine strategy, which also provided full protection against pneumonic plague to mice lacking IFN-α, IFN-β, and IFN-γ receptors. Depletion of IFN-γ or tumor necrosis factor-α from immunized WT mice before and during infection did not reduce protection against pulmonary Y. pestis CO92 challenge. These data suggest that IFN-γ may not be required for protection against pneumonic plague by these vaccines. Combining live-attenuated and adenovirus-based vaccines resulted in augmentation of systemic and local immune responses, which could be beneficial in providing long-lasting immunity against pneumonic plague.
2026-02-25 | An adenoviral-vectored vaccine protects mice against aerosol challenge with Yersinia pestis.
With the success of viral-vectored vaccines against Ebola and SARS-CoV-2, these platforms are now established as promising tools for biodefence against outbreak pathogens. Here, we report the development of adenoviral-vectored vaccines against plague, caused by Yersinia pestis. Replication-deficient adenoviral-vectored constructs expressing the protective Y. pestis antigens F1 and LcrV, alone or in combi and combinations thereof were created. Expression of the antigens was confirmed in vitro, and immunogenicity assessed in mice. Protective efficacy was evaluated using a virulent Y. pestis aerosol challenge model in mice. All vaccine candidates induced high serum IgG antibody responses. Notably, the antibody responses were similar when vectors expressing different antigens were mixed or when using a single vector expressing a chimeric fusion of the two antigens. All of the six experimental vaccine formulations tested via intramuscular injection containing either the V gene or purified V protein provided 90%-100% protection from mortality due to inhalational infection with Y. pestis. Notably, only the human adenovirus 5 construct expressing a full length F1-V fusion provided 100% protection from both morbidity and mortality after a single dose. In contrast, naive mice and 50% of mice immunized with two doses of the recombinant proteins with adjuvant displayed clinical signs of illness (morbidity) despite protection from mortality. Importantly, in a follow-up virulent aerosol challenge study, a single dose of ChAdOx1 F1-V fusion provided protection comparable to that achieved with HuAd5 vaccine. Based on these results, a ChAdOx1 F1-V fusion vaccine has progressed to phase I human clinical trials.
2026-01-28 | Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing.
Yersinia pestis caused the three plague pandemics that claimed more than two hundred million human lives. There is still no vaccine that meets all WHO requirements, and many researchers continue to develop plague vaccines using various technological platforms. For example, researchers led by Roy Curtiss 3rd have developed a new approach to achieve controlled, delayed attenuation of bacterial pathogens. Mutants generated using this method were superior in protecting Y. pestis-infected mice immunized with strains generated using traditional gene knockout. However, further studies are needed to determine the safety and efficacy of these delayed-attenuated strains in other mammalian species in order to extrapolate on humans the data obtained in accordance with the FDA Animal Rule. Three Y. pestis strains, a Δcrp mutant, a mutant with arabinose-dependent regulated crp expression (araC PBADcrp) or an araC PBADcrp mutant cured of plasmid pPst were derived from virulent wild-type strain 231. To evaluate the safety, outbred mice or guinea pigs were immunized subcutaneously with serial tenfold dilutions of mutated strains. For vaccine studies, immunized animals were subcutaneously challenged with 200 LD100 (lethal dose in all exposed subjects) of the wild-type Y. pestis strain. The challenge caused the death of 100% of naïve animals in controls. The Y. pestis strain 231Δcrp was nonlethal in mice at a dose of 107 CFs. The LD50 of the 231Δcrp strain in guinea pigs increased by at least 107-fold compared to that of the wild-type strain. The LD50s of the 231PBAD-crp mutant in mice and guinea pigs were approximately 104-fold and 107-fold higher than those of Y. pestis 231, respectively. The 231PBAD-crp(pPst¯) strain did not cause death in mice (LD50 > 107 CFU) and guinea pigs (LD50 > 109 CFU) when administered subcutaneously and was capable of inducing intense protective immunity in both species of laboratory animals. Our research has shown once again the necessity of balance between safety and effectiveness demonstrating the feasibility of further investigation of crp mutants as promising candidate plague vaccines.
2026-01-14 | Intranasal unadjuvanted LcrV boosts parental Yersinia OMV primed lung immunity against pneumonic plague in mice.
Pneumonic plague remains a high-consequence respiratory disease, highlighting the need for vaccines that induce durable lung-localized immunity. We show that intramuscular prime-boost vaccination with Alum-absorbed OMV46-LcrV (OMV46-LcrV/Alum) is safe but provides limited long-term protection against respiratory Yersinia pestis challenge in mice. To enhance lung immunity, we deliver an adjuvant-free intranasal LcrV "spike" following IM OMV46-LcrV/Alum priming. This "prime-spike" regimen is well tolerated and confers complete short- and long-term protection against high-dose pulmonary Y. pestis challenge. The approach increases lung resident memory B cells, including antibody-secreting cells, and resident memory T cells with elevated Interferon-γ, Interleukin-17A, and Interleukin-4 production. These localized memory responses contribute to improved protection, demonstrating the promising potential of prime-spike immunization for combating pneumonic plague.
2025-09-20 | Lipid A mimetic BECC438 potentiates durable and balanced antibody responses in an ovalbumin murine model of vaccination.
The need for effective infectious disease vaccines has become an inescapable topic in recent years. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include adjuvants that avoid excessive adverse reactions while allowing for dose and antigen sparing. Bacterially derived TLR4 agonist, BECC438, has recently emerged as a lead adjuvant candidate across several experimental models of infectious disease, including Yersinia pestis (plague), human papillomavirus, influenza A (flu), SARS-CoV-2 (COVID-19), and Shigella spp (gastrointestinal infection). To confirm that BECC438 is a high-quality immunoadjuvant, even without antigen from an infectious pathogen, studies presented here use the model antigen ovalbumin in a murine prime-boost vaccine model. Durable and more balanced production of antibody isotypes IgG1 and IgG2 is observed when the bacterial enzyme combinatorial chemistry adjuvant is used, as compared with the classic adjuvants aluminum salts (Alhydrogel) and synthetic monophosphorylated lipid A-PHAD (phosphorylated hexaacyl disaccharide). Antibody responses are maintained for at least 18 wk postvaccination. Observed immune metrics maintained similar trends across males, females, and genetic backgrounds, including C57BL/6, BALB/c, and CD-1 (outbred) mice, with males overall showing a lower production of IgG2c. In vitro analysis of C57BL/6 serum showed an increased half-life of ovalbumin-specific antibodies in BECC438 adjuvanted animals, indicative of a higher antigen binding affinity. These studies provide continued evidence to support the development of the BECC438 adjuvant in vaccines for human use.
proteins
2026-06-17 | Spatiotemporal dynamics of the capture rate of Rattus tanezumi and its implications for rodent-borne diseases in the Three Gorges Reservoir Area, China.
Rattus tanezumi (R. tanezumi) is a major amplifying host for plague and an important reservoir host for multiple zoonotic pathogens, including leptospirosis and hantavirus. Its population dynamics in the Three Gorges Reservoir (TGR) Area of China are influenced by climate and reservoir-induced environmental changes, thereby impacting disease transmission risks. Based on rodent capture rate data collected using cage traps during night surveys in January, March, May, July, September, and November each year from 2015 to 2021, this study investigated the spatiotemporal dynamics of R. tanezumi and its association with key meteorological and environmental factors. Using Geographic Information Systems (GIS) for spatiotemporal analysis and a Generalized Additive Model (GAM), we identified the current month's average temperature and relative humidity, together with 3-month-lagged precipitation and the Normalized Difference Vegetation Index (NDVI), as associated factors. The highest capture rate occurring at around 20 °C. Rat capture rate negatively correlated with both current relative humidity and lagged precipitation and a fluctuating decline with increasing lagged NDVI. This study demonstrates how climatic and environmental factors shape the spatiotemporal distribution of R. tanezumi population in the Three Gorges Reservoir Area. These findings provide insights that may inform predictions of rodent‑borne disease risks and support the development of targeted surveillance and control strategies in this ecologically vulnerable region.
2026-05-13 | Evolutionary trends of plague research from 2016 to 2025: A bibliometric analysis.
Plague is a severe zoonotic disease caused by Yersinia pestis, a pathogen characterized by high infectivity and mortality rates. Historically, three global pandemics have inflicted heavy disasters on human society. Despite improvements in control measures and the application of antibiotics, plague has been somewhat controlled; however, since the beginning of the 21st century, plague outbreaks have continued to occur in regions with a high burden of neglected tropical diseases (NTDs) in Africa, the Americas, and Asia. In recent years, the rapid development of technologies such as molecular biology, immunology, and bioinformatics has propelled significant advancements in plague diagnostics, vaccine development, and transmission mechanisms. However, there has been a lack of systematic quantitative analysis of the distribution characteristics, evolving hotspots, and frontier trends of plague research, which makes it challenging to provide comprehensive scientific support for research and control decision-making. Search for relevant literatures on plague that were published in the Web of Science Core Collection and PubMed database from January 1, 2016 to November 12, 2025.Bibliometric methods were adopted, and software including COOC 20.6, VOSviewer 1.6.20, and Anaconda were used to analyze the publication trend, distribution of institutions, national cooperation network, keyword co-occurrence clustering, and the annual variation trends. A total of 1994 documents were finally included. The annual number of publications showed an overall fluctuating upward trend, with a significant growth rate from 2020 to 2021 (annual growth rate of 10.44%). Core research institutions included the U. S. Centers for Disease Control and Prevention and Beijing Institute of Microbiology and Epidemiology. The United States, China, France and Madagascar were the main core countries for cooperation. Keyword co-occurrence clustering identified five major research fields, which were plague vaccine development and immune mechanism, ecology and vector control, historical epidemiology and public health, epidemiology and transmission chain, and plague-related infectious diseases and biosafety. The research trends analysis showed that from 2016 to 2020, the plague research mainly focused on keywords such as "Rodents" "Epidemiological Survey" "Human Plague" and "Fleas". From 2021 to 2025, "Phylogenetic Analysis," "Public Health," and "Madagascar" newly entered the top 20 keyword list; the frequencies of "Black Death" and "Infectious Disease" increased significantly, while the frequencies of "Plague Vaccine" and "Prairie Dogs" remained relatively stable. Over the past decade, remarkable achievements have been made in plague research. Interdisciplinary integration and technological innovation have continued to deepen. However, global collaboration remains insufficiently developed. In the future, it is necessary to foster broader cross-regional cooperation, accelerate the research, development and translation of vaccines and diagnostic technologies, integrate multiple technologies to construct a precise prevention and control system. and enhance the global collaborative prevention and control capabilities of plague.
2026-03-07 | Application of Long-Read Sequencing for Genotyping, Epigenetic Profiling and Surveillance of Yersinia pestis Isolates from Natural Foci and Disease Outbreaks in Central Asia.
This study explores the application of long-read sequencing technologies for genotyping, epigenetic profiling, and epidemiological monitoring of Yersinia pestis isolates obtained from natural foci in Central Asia and previous zoonotic outbreaks. Computational tools for genome assembly and genotyping were developed, enabling high-precision identification of both chromosomal and plasmid sequences, including the small plasmid pCKF. Genotyping based on genetic polymorphisms distinguished the major Y. pestis biovars and lineages, and revealed cluster-specific diversity among Medievalis (2.MED) isolates, including groups of strains associated with different plague foci and disease outbreaks in domestic animals and humans. These specific genomic polymorphisms identified in subclades of 2.MED isolates allow their high-precision identification. The distribution of pCKF-positive strains in the region and the potential involvement of these pathogens in disease outbreaks are discussed. Additionally, comparative epigenomic analysis uncovered strain-specific cytosine methylation patterns at cgGATCG motifs. Further studies involving more sequenced strains are needed to determine whether this cytosine methylation specificity is linked to genome function regulation and adaptation to different hosts and environments. These findings demonstrate the effectiveness of long-read sequencing technologies in revealing both genetic and epigenetic features of bacterial pathogens, contributing to our understanding of the evolutionary mechanisms underlying the emergence and spread of this especially dangerous infection.
2026-01-22 | Imperial Careering: India and the Women's Medical Movement, 1896-1920.
India figured prominently in the women's medical movement of the late nineteenth and early twentieth centuries. It was both a cause-bringing medical aid to Indian women-and a career-offering employment opportunities to qualified British women doctors. Where most studies have focussed on the early years of the movement in India and the creation of the Dufferin Fund in 1885, this article explores the careers, attitudes and experiences of a second generation of white women doctors, from the outbreak of bubonic plague in 1896 to the end of the First World War. As an exercise in imperial careering, it charts the parallels and connections between women doctors in India and Britain but also assesses the obstacles to the pursuit of medical careers in India and the factors, personal, political and professional, that by 1920 were driving women's medicine in metropole and empire further apart.
2026-01-16 | Commentary on Seersholm Et al.: Yersinia pestis Infection Is Not Synonymous With Deadly Plague in Neolithic Scandinavia.
Emerging genomic evidence has identified ancestral strains of Yersinia pestis in ancient human populations, which has sparked debates about its pathogenic role in later Neolithic societies. Here, we review published evidence linking anthropological and biological data reflecting the past natural history of Y. pestis infection. Review of reported ancient Y. pestis genomes, paleomicrobiological, archaeological, and ecological data related to ancient plague. While some researchers attributed the Scandinavian Neolithic population decline to plague epidemics, we argue that early Y. pestis strains were more likely associated with outbreaks of food-borne enteritis rather than flea-borne plague. This hypothesis is supported by genetic, archaeological, and ecological analyses, which indicate that Y. pestis evolved key flea-borne transmission mechanisms only later in its history.
small molecules
2026-08-17 | The 1820 Mallorca plague was not a classic bubonic outbreak.
The 1820 plague outbreak in eastern Mallorca-long treated as a local episode and traditionally classified as a late bubonic manifestation of the Second Plague Pandemic-offers a unique opportunity to reassess transmission dynamics in a prebacteriological context. Using a previously unexamined primary source consisting of daily counts of deaths, we combine historical analysis with a Bayesian epidemiological model to estimate the basic reproduction number ([Formula: see text]), the mean infectious period, and the case-fatality ratio in the towns of Son Servera and Capdepera (Mallorca, Spain). Our results show stark contrasts between the two towns: Son Servera exhibited a higher transmission potential ([Formula: see text]) and longer infectious period ([Formula: see text]2.8 d) than Capdepera ([Formula: see text]; [Formula: see text]2.0 d). The overall case-fatality rate of 78%-together with short infectious periods and historical descriptions of rapid clinical decline-strongly suggests that pneumonic and septicemic forms contributed substantially to transmission, challenging earlier interpretations centered on bubonic plague and rodent-borne spread. Historical evidence also rules out an enzootic rat reservoir, pointing instead to human ectoparasites or direct human-to-human routes as the most likely drivers. Moreover, mortality among children increased significantly during the outbreak, indicating age-differentiated vulnerability. By integrating quantitative modeling with fine-grained archival records, this study reassesses the biological nature of one of the last major plagues in 19th-century western Europe and contributes to broader debates on plague ecology, transmission mechanisms, and the dynamics of late Second Pandemic outbreaks.
2026-05-13 | Fipronil Baits as Emerging Tools for Flea Control and Plague Mitigation: Experiments with Cricetid Mice on Prairie Dog Colonies.
Plague is a zoonotic disease of mammalian hosts and flea vectors. Wildlife biologists most commonly mitigate plague by controlling flea populations. We evaluated the efficacy of edible baits for systemic flea control with two cricetid species on colonies of black-tailed prairie dogs (Cynomys ludovicianus): the western deer mouse (Peromyscus sonoriensis) and the northern grasshopper mouse (Onychomys leucogaster). We tested grain bait with 0.005% fipronil by weight and "FipBit" pellets with 0.46-1.52 mg of fipronil/pellet. Flea prevalence was assessed via combing of live-trapped mice. In one experiment with fipronil grain bait and FipBits (n=564 combings), flea prevalence declined from 74% (grain) and 45% (FipBits) before treatments to 0% for both treatments from 30-44 d and from 324-413 d after treatments. During a second experiment with FipBits (n=299 combings), flea prevalence declined from 13% to 32% before treatments to 0% from 11-15 d after treatments, but increased to 29-56% from 349-378 d after treatments. Results herein suggest annual fipronil bait treatments may be most effective for flea control.
2026-03-26 | Edible baits for systemic flea control, plague mitigation, and wildlife conservation: evaluation of four active ingredients with three rodent species in western North America.
The flea-borne agent of plague, Yersinia pestis, is lethal to endangered black-footed ferrets (Mustela nigripes, BFFs) and the prairie dogs (Cynomys spp., PDs) on which BFFs depend for habitat and prey. We developed bait pellets containing insecticides for flea control with PDs. Individual baits contained 0.46, 0.91, 1.21, or 1.52 mg fipronil, 5.40 mg afoxolaner, 50.62 mg fluralaner, or 85.20 mg spinosad. From 2023 to 2025, we tested the baits with black-tailed PDs (C. ludovicianus, BTPDs), Gunnison's PDs (C. gunnisoni, GPDs), and Richardson's ground squirrels (Urocitellus richardsonii, RGSs). We sampled hosts 2810 times and detected 8825 fleas across 2 U.S. States, 1 Canadian Province, 6 sites, 9 PD colonies, and 41 sampling plots. Over ∼12 mo across 5 replicates in South Dakota, USA, bait pellets with 0.91 or 1.52 mg fipronil, applied at a rate of 125 baits/ha, were more effective in reducing the abundance of fleas on BTPDs than 0.46 mg fipronil or the 3 other active ingredients; on 2 South Dakota replicates with data from 24 mo posttreatment, the effects of fipronil pellets on flea abundance had waned after ∼24 mo. Similarly, over ∼12 mo on 2 replicates in Arizona, USA, pellets with 1.52 mg fipronil were more effective in reducing the abundance of fleas on GPDs than pellets with 0.46 mg fipronil; on 1 replicate with available data from ∼2 yr posttreatment, the effects of fipronil pellets had waned after ∼24 mo. Over ∼8-11 mo across 2 replicates in Saskatchewan, Canada, baits with 1.21 mg fipronil/pellet were more effective in suppressing the abundance of fleas on BTPDs and RGSs when applied at 250 pellets/ha than 62 pellets/ha; flea control had waned after ∼20-23 mo. When applied annually at 125-250/ha, baits with 0.84-1.52 mg fipronil (FipBits) provided an effective, efficient, and affordable tool for flea control on PD colonies.
2026-03-01 | PLAGUE IN THE 21ST CENTURY: GLOBAL OVERVIEW AND PERSPECTIVES IN BRAZIL
Yersinia pestis , the causative agent of plague, evolved from Y. pseudotuberculosis about 6,000 years ago and remains a relevant zoonotic pathogen in the 21st century. Although associated with major historical pandemics, a significant number of human cases are still reported annually, resulting in hundreds of deaths from its most notable forms, bubonic and pneumonic. Knowledge of the epidemiology of this infection is therefore essential for healthcare professionals in the differential diagnosis of febrile syndromes. To estimate the current prevalence of human Y. pestis infections and to evaluate plague case fatality rates in its most common forms. A literature review was conducted exclusively in the PubMed/PMC database, including epidemiological studies, case series, and surveillance analyses published between 1990 and 2023. Articles presenting quantitative data on human cases, regional distribution, and case fatality rates were selected. Between 2000 and 2010, 21,725 plague cases and 1,612 deaths were reported globally, resulting in an approximate case fatality rate of 7.4%. In the United States, from 1900 to 2012, 1,006 cases were recorded, with a recent average of seven cases per year, mainly concentrated in the western states. In Brazil, active bubonic plague foci persisted until the 1960s, totaling more than 2,000 documented cases between 1936 and 1956. Studies identified continued presence of Yersinia pestis in rodents and fleas in the Northeast until 2005, maintaining potential risk of reemergence, although no recent human cases have been reported. Entomological and animal surveillance remains active in these regions. Regarding severity, the case fatality rate for treated bubonic plague is around 8–10%, while for pneumonic plague, without rapid intervention, it can exceed 50%. These data reinforce that although plague is currently rare, it remains a relevant zoonosis, especially in areas with confirmed circulation of Yersinia pestis in wild reservoirs. The high lethality of pneumonic forms and persistence of natural foci, as historically observed in Brazil and still present in other regions worldwide, make the maintenance of continuous epidemiological surveillance, environmental monitoring, and rapid response strategies indispensable to prevent reemergence.
2026-01-20 | Structural and Biophysical Characterization of the Yersinia Type Three Secretion System ATPase YscN.
Yersinia pestis was responsible for the Black Plague, one of the worst epidemiological disasters in recorded history. Today, Y. pestis , Y. enterocolitica , and Y. pseudotuberculosis remain clinically relevant human pathogens. Each of these pathogenic Yersinia species relies on a Type Three Secretion System (T3SS) for virulence, with the ATPase YscN playing a critical role in T3SS function. T3SS ATPases are responsible for powering apparatus formation and effector protein secretion through ATP hydrolysis. This study provides an extensive enzymatic characterization of recombinant YscN under several conditions, including variable pH and temperature, substrate and protein concentrations, and in the presence of putative inhibitors. Thermal stability data, assessed by circular dichroism, demonstrate that YscN exhibits increased stability in alkaline conditions, coinciding with greatest ATPase activity. Further, we report the first high-resolution crystal structure of YscN and leverage homology data to model an oligomeric active site. Mutational analysis of a predicted active site residue confirms oligomerization as necessary for YscN ATPase activity and corroborates our oligomeric model and enzyme concentration-dependent specific activity. Interestingly, however, AUC analysis reveals that the purified YscN predominantly exists as a monomer, despite oligomerization-dependent active site formation. Thus, we propose that transient oligomeric interactions support the observed ATP hydrolysis. Together, these data uncover structural and environmental impacts on YscN activity that may support the highly specialized Yersinia pathogenic lifecycle and leverage its role in virulence in search of pan-effective small molecule T3SS ATPase inhibitors.
antibodies
2026-07-08 | Protective outcomes of high-affinity monoclonal antibodies against drug-resistant plague strains.
Yersinia pestis, a category A infectious organism, is known to cause bubonic, septicemic, and pneumonic plague. With the emergence of streptomycin-resistant strains, there is an urgent need for new therapeutic strategies that can protect populations from Y. pestis infection. The main strategy for developing vaccines and therapeutic antibodies involves F1 antigen. Previous research has demonstrated that both human and murine monoclonal antibodies(mAbs) confer protective effects against Y. pestis infection. While, no relevant studies were identified on mAbs against drug-resistance Y. pestis. Here, we constructed an antibody library from Y. pestis vaccine strain EV76-immunized mice by phage display. The mAbs were baited by recombinant F1 antigen, and the biological functions of the obtained mAbs were assessed and evaluated in plague-challenged mice. For the Y. pestis strain 141 group, both Fm3 and Fm25 provided 100% protection at a dose of 100 µg. At 20 µg, only Fm3 conferred partial protection, with a survival rate of 25%, whereas all mice in the 4 µg treatment groups succumbed to infection within approximately 10 days. Against the drug-resistant Y. pestis strain S19960127, Fm25 at 100 µg resulted in complete survival, whereas Fm3 at the same dose conferred 75% protection. Neither mAbs showed protective efficacy at 20 µg or 4 µg, and all animals dying within approximately 10 days post-infection. These findings indicated that mAbs Fm3 and Fm25 confer protection against virulent and drug-resistant strains of Y. pestis.
2026-06-23 | Table 1_Protective outcomes of high-affinity monoclonal antibodies against drug-resistant plague strains.doc
Background Yersinia pestis, a category A infectious organism, is known to cause bubonic, septicemic, and pneumonic plague. With the emergence of streptomycin-resistant strains, there is an urgent need for new therapeutic strategies that can protect populations from Y. pestis infection. The main strategy for developing vaccines and therapeutic antibodies involves F1 antigen. Previous research has demonstrated that both human and murine monoclonal antibodies(mAbs) confer protective effects against Y. pestis infection. While, no relevant studies were identified on mAbs against drug-resistance Y. pestis. Methods Here, we constructed an antibody library from Y. pestis vaccine strain EV76-immunized mice by phage display. The mAbs were baited by recombinant F1 antigen, and the biological functions of the obtained mAbs were assessed and evaluated in plague-challenged mice. Results For the Y. pestis strain 141 group, both Fm3 and Fm25 provided 100% protection at a dose of 100 µg. At 20 µg, only Fm3 conferred partial protection, with a survival rate of 25%, whereas all mice in the 4 µg treatment groups succumbed to infection within approximately 10 days. Against the drug-resistant Y. pestis strain S19960127, Fm25 at 100 µg resulted in complete survival, whereas Fm3 at the same dose conferred 75% protection. Neither mAbs showed protective efficacy at 20 µg or 4 µg, and all animals dying within approximately 10 days post-infection. Conclusion These findings indicated that mAbs Fm3 and Fm25 confer protection against virulent and drug-resistant strains of Y. pestis.
2026-02-23 | Pulmonary delivery of a humanized heavy-chain antibody LcrV-X19-R1 confers complete protection against fatal pneumonic plague in mice.
Pneumonic plague is the most fatal form of plague, with a mortality rate approaching 100% within 24 h if untreated. The emergence of drug-resistant Yersinia pestis strains capable of human-to-human transmission poses a significant challenge to conventional antibiotic therapies. While therapeutic antibodies present a promising alternative, their intravenous administration is limited by low pulmonary bioavailability and suboptimal efficacy. Targeting LcrV, a key virulence factor of Yersinia pestis type III secretion system, we developed a humanized heavy-chain antibody designated LcrV-X19-R1, and formulated it for inhalation delivery. LcrV-X19-R1 exhibited a high affinity for LcrV (KD of 0.561 nM), demonstrated good thermal stability, produced inhalable aerosol particles with a mass median aerodynamic diameter of ≤5 μm after nebulization, and showed a favorable safety profile in vivo, with all these properties meeting the criteria for effective pulmonary deposition. In a lethal mouse model of pneumonic plague, pulmonary delivery of LcrV-X19-R1 achieved 100% survival, completely cleared the bacterial loads in organs, and markedly reduced tissue damage. The protective mechanism of LcrV-X19-R1 involves direct bacterial neutralization in tissues and enhanced clearance via antibody-dependent cellular phagocytosis, which together dampen harmful inflammation and promote tissue repair. Pharmacokinetically, pulmonary delivery achieved roughly 10-fold higher lung antibody levels and retention beyond 120 h, far surpassing intravenous administration. These advantages ultimately translated into a 70% survival rate, compared to 0% with intravenous treatment. This study establishes a mucosal therapeutic strategy against pneumonic plague and provides a versatile platform for developing antibody-based interventions against other respiratory infectious diseases.
2024-12-16 | Human genetic variation reveals FCRL3 is a lymphocyte receptor for Yersinia pestis.
Yersinia pestis is the gram-negative bacterium responsible for plague, one of the deadliest and most feared diseases in human history. This bacterium is known to infect phagocytic cells, such as dendritic cells and macrophages, but interactions with non-phagocytic cells of the adaptive immune system are frequently overlooked despite the importance they likely hold for human infection. To discover human genetic determinants of Y. pestis infection, we utilized nearly a thousand genetically diverse lymphoblastoid cell lines in a cellular genome-wide association study method called Hi-HOST (High-throughput Human in-vitrO Susceptibility Testing). We identified a nonsynonymous SNP, rs2282284, in Fc receptor like 3 (FCRL3) associated with bacterial invasion of host cells (p=9×10-8). FCRL3 belongs to the immunoglobulin superfamily and is primarily expressed in lymphocytes. rs2282284 is within a tyrosine-based signaling motif, causing an asparagine-to-serine mutation (N721S) in the most common FCRL3 isoform. Overexpression of FCRL3 facilitated attachment and invasion of non-opsonized Y. pestis. Additionally, FCRL3 colocalized with Y. pestis at sites of cellular attachment, suggesting FCRL3 is a receptor for Y. pestis. These properties were variably conserved across the FCRL family, revealing molecular requirements of attachment and invasion, including an Ig-like C2 domain and a SYK interaction motif. Direct binding was confirmed with purified FCRL5 extracellular domain. Following attachment, invasion of Y. pestis was dependent on SYK and decreased with the N721S mutation. Unexpectedly, this same variant is associated with risk of chronic hepatitis C virus infection in BioBank Japan. Thus, Y. pestis hijacks FCRL proteins, possibly taking advantage of an immune receptor to create a lymphocyte niche during infection.
2024-11-22 | From the ports to the hinterland. Plague, bacteriology, and politics in Argentina (1899-1940).
In 1899, the first cases of plague were recognised in Paraguay and a few months later in Buenos Aires as part of the third plague pandemic. In the first decades of the twentieth century, plague slowly advanced towards the Argentinian hinterland. In this paper we focus on the production of scientific knowledge about plague in Argentina, where a core of bacteriologists emerged early on. We show how they not only played a central role in the complex process of plague recognition and intervention, but also influenced the scientific development of bacteriology in Argentina and potentially in South America. We argue that bacteriology became a key tool in articulating the promises of modern science with political and economic interests, allowing the Argentinian government to extend its territorial control over Buenos Aires and the hinterland. This can be seen in two different configurations of the plague as an epistemic and political object in Argentina. In the first period, from 1899 to 1910, plague was a problem linked to the ports. In this section of the article, we show how plague became an important issue in the development of bacteriology in Argentina, how this research contributed to new intervention measures and, in some cases, developed innovative ideas about serotherapeutic treatments and the characteristics of the disease. In the second period, from the mid-1910s until the 1940s, research in Argentina provided new evidence of the 'rural' nature of plague, a process in deep dialogue with research on plague among peri-domestic and wild rodents carried out in other parts of the Americas, Europe and Africa. This article thus aims to contribute to a history of bacteriology that highlights the role of non-European centres, like Argentina, in the production and circulation of bacteriological knowledge.
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2026-05-13 | Targeting Undruggable Protein Interactions with DNA Aptamers: Inhibition of the Interaction Between Yersinia Outer Protein M and Human DEAD-Box Helicase 3.
The plague, caused by Yersinia pestis, has resulted in significant mortality over the past century. Despite advances in antimicrobial therapy, plague remains a re-emerging infectious disease with ongoing outbreaks and increasing concerns regarding antimicrobial resistance. Today, plague cases are still being reported, and the loss of effectiveness of treatment methods remains a major challenge. Therefore, effective treatment strategies are needed. In this study, we aimed to develop aptamers specific to Yersinia outer protein M (YopM), a key immunosuppressive protein that is essential for virulence. Our goal was to develop an aptamer that binds to YopM and inhibits its interaction with the human DEAD-box helicase 3 (DDX3) protein. YopM-DDX3 protein interaction was targeted because of its key role in nucleocytoplasmic shuttling of YopM. To achieve this, we developed the YopM16 aptamer using magnetic bead-based (Systematic Evolution of Ligands by Exponential Enrichment) (SELEX). The selected YopM16 aptamer exhibited a half-maximal inhibitory concentration(IC50) value of 103.3 ± 2 nM and effectively inhibited the interaction between YopM and DDX3. The inhibitory effect of the aptamer on protein interaction was confirmed using a pull-down assay and colorimetric test. Given that protein-protein interaction surfaces are considered undruggable, YopM16 is a promising inhibitor with the potential to serve as a molecular tool to investigate the virulence mechanism of YopM, as well as a novel antibacterial agent upon validation of its inhibition in cellular models.
2026-01-23 | Inhalable DNA nano-adjuvant elicits robust lung-resident memory immunity against pneumonic plague.
Pneumonic plague, caused by Yersinia pestis, remains a deadly threat due to its high mortality and rapid progression. In our previous study, Yersinia pestis antigens formulated with CpG oligodeoxynucleotides show great potential against pneumonic plague, but these agonists display low TLR9 affinity, poor stability, limited cellular uptake, and weak induction of tissue-resident memory immunity. Here, we introduce AdjCRU, a cruciform DNA nano-adjuvant built on a four-way junction with each arm presenting looped CpG motifs (LoDNA) for TLR9 engagement. Guided by computational design and molecular dynamics simulations, the four-way junction is chosen over other nanostructures for superior TLR9 binding. AdjCRU is nuclease-resistant, prepared by one-step annealing of four single-stranded oligonucleotides. When administered via aerosolized intratracheal inoculation alongside Yersinia pestis recombinant antigen rV10, AdjCRU is effectively internalized into lysosomes of antigen-presenting cell (APC), inducing markedly enhanced APC maturation, germinal center reaction, systemic and mucosal antibody titers, and T/B cell activation. Notably, rV10+AdjCRU drives robust lung-resident memory T/B cell immunity, and significantly improves survival by 40 % over free LoDNA in a lethal pneumonic plague mouse model. By integrating programmability, biocompatibility, and enhanced TLR9 stimulation into a single, modular platform, AdjCRU offers a versatile strategy for next-generation mucosal adjuvants against respiratory pathogens.
2025-10-29 | Plagued by the Past, Pressed by the Present: A One Health Perspective on Yersinia pestis.
Yersinia pestis, the causative agent of plague, is arguably the most devastating pathogen in human history. Paleogenomic studies indicate its presence as early as the Neolithic era. It evolved from Yersinia pseudotuberculosis, with divergence estimates ranging from 1500 to 20,000 years ago, most often placed around 5000 years ago. Its natural reservoirs are wild mammals, particularly rodents, with fleas serving as vectors, while humans are incidental hosts. Over time, Y. pestis has acquired multiple virulence factors that disrupt immune responses and can lead to rapid, often fatal disease. Because the bacterium is maintained in wildlife cycles and can spill over to domestic animals, eradication is difficult, if not impossible. Nevertheless, mitigation is achievable using a One Health approach integrating human health, animal health, and the health of the environment. Neither vaccines nor monoclonal antibodies are currently licensed in most Western countries, thus, antibiotics remain the mainstay of therapy. Timely administration, ideally within 24 h of symptom onset, is critical, particularly in pneumonic forms. Phage therapy is under investigation as a potential treatment. Though often neglected in high-income settings, plague remains endemic in several regions, with the highest burden reported in Madagascar and the Democratic Republic of the Congo.
2025-07-09 | Rapid adaptation to a globally introduced virulent pathogen in a keystone species.
Emerging infectious diseases are one of the foremost contemporary threats to biodiversity conservation. Outbreaks of novel pathogens can lead to the extinction of host populations, loss of gene flow due to extirpation, and bottlenecks in host populations with surviving individuals. In outbreaks with survivors, pathogens can exert strong selection on hosts, in some cases leading to the evolution of resistance or tolerance in the host population. The pathogen causing sylvatic plague, Yersinia pestis, was introduced to North America in the early 1900s and caused widespread population declines in prairie dogs (genus Cynomys), which experience >95% mortality during epizootics. Recently, survival from plague was documented in a small number of black-tailed prairie dogs (Cynomys ludovicianus) in natural populations in Colorado (United States). We performed whole-genome sequencing on all seven individuals that survived infection with plague and seven individuals that likely died. Using genome-wide association tests, F ST outlier tests, and other inferences of selection, we detected single nucleotide polymorphisms (SNPs) on five scaffolds that were strongly associated with survivorship from plague in nature. One candidate gene, inducible T-cell stimulator (ICOS), was also associated with survival in humans during the Black Death in London (United Kingdom), suggesting conservation of gene function across taxonomically diverse lineages. In addition, three candidate genes (TMEM198, PCDHB12/15, and KIAA1191) are different from but in the same gene classes (transmembrane proteins, protocadherins, and Kasuza protein-binding genes) as candidate genes for plague resistance in great gerbils, providing support for the hypothesis that parallel evolution may occur at the level of gene classes in addition to individual genes. Understanding the genomic basis of immunity can enable genetically informed management actions, such as targeted relocation to protect grassland species. Moreover, understanding how rapid adaptation to pathogens occurs can help us predict the time frame and spatial scale at which adaptation may occur, during which other interventions are needed.
2025-05-29 | Attenuation of virulence in Yersinia pestis across three plague pandemics.
Yersinia pestis has spilled over from wild rodent reservoirs to commensal rodents and humans, causing three historically recorded pandemics. Depletion in the copy number of the plasmid-encoded virulence gene pla occurred in later-dated strains of the first and second pandemics, yet the biological relevance of the pla deletion has been difficult to test. We identified modern Y. pestis strains that independently acquired the same pla depletion as ancient strains and herein show that excision of pla from the multicopy pPCP1 plasmid is accompanied by the integration of a separate full pPCP1 harboring pla into the single-copy pCD1 plasmid, reducing pla dosage. Moreover, we demonstrate that this depletion decreases the mortality of mice in models of bubonic plague but not in the pneumonic and septicemic forms of the disease. We hypothesize that pla depletion may have been selectively advantageous in bubonic plague, owing to rodent fragmentation after pandemic-induced mortality.
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Drug Discovery Landscape
3 orphan drug designations for Plague.
3 orphan drug designations for Plague.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
rF1V Vaccine with CpG 1018 | vaccines | FDA | 2026-08-17 | — | Dynavax Technologies Corporation |
Yersinia pestis plague recombinant antigen (rF1V; F1 capsular protein fused to V antigen; E. coli) vaccine with aluminum hydroxide | vaccines | FDA | 2016-11-30 | — | The Surgeon General, Department of the Army |
cethromycin | small molecules | FDA | 2009-09-09 | — | Advanced Life Sciences, Inc. |
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