Yersinia pestis, the etiological agent of bubonic, pneumonic, and septicemic plague, remains a pathogen of high consequence despite advances in public health and antimicrobial therapy. From early empirical antisera and whole-cell vaccines in the late 19th and early 20th centuries to heat-killed vaccines used in high-risk populations, scientific efforts have steadily refined our understanding of this organism’s complex pathogenicity. Contemporary research now recognizes Y. pestis as a multi-system pathogen capable of systemic, pneumonic, gastrointestinal, and neurological involvement, driven by a sophisticated arsenal of virulence factors and immune evasion strategies. Parallel progress in immunology, genomics, structural biology, and systems biology—augmented by emerging artificial intelligence platforms such as the RAPTOR program and related tools—is transforming how researchers interrogate host–pathogen interactions, predict antigenic targets, and design rational vaccines and therapies. Together, these advances keep plague squarely within the remit of high priority infectious threats, especially in the context of antimicrobial resistance, zoonotic reservoirs, climate-driven ecological shifts, and biodefense concerns.

This article collection focuses on the evolution of plague vaccines and therapeutics from the pioneering work of Yersin and early antisera to modern subunit, recombinant protein, RNA-based, and nanoparticle enabled candidates. We highlight cutting-edge technologies including self-amplifying RNA (saRNA) platforms, combination regimens (such as RNA priming with viral vector or protein boosts), advanced adjuvants, and depot-formulated cytokine approaches designed to elicit durable and protective immunity. The collection also emphasizes innovative in vivo models (mouse, rat, ferret, and the prospects for human challenge models) and in vitro systems that are reshaping our understanding of plague immunology and immunopathogenesis. By integrating data on therapeutic antibodies, nanobodies, phage-based interventions, novel antibiotics, and next-generation prophylaxis strategies, we aim to provide a comprehensive view of the current landscape—from basic mechanisms of virulence and immune evasion to candidate vaccines and therapies advancing toward WHO Target Product Profile (TPP) alignment, emergency use authorization, and eventual licensure.

We welcome submissions including, but not limited to:

• Historical perspectives on the evolution of plague vaccines and antisera, from Yersin’s early work through heat killed vaccines to modern subunit and recombinant platforms

• Structure–function studies of Y. pestis virulence factors (e.g., F1, V antigen, YscF, T3SS components) that inform antigen selection and vaccine design

• Mechanistic insights into Y. pestis pathogenesis across systemic, pneumonic, gastrointestinal, and neurological disease, and their implications for medical countermeasures

• Studies elucidating the immunology and immunopathogenesis of plague, including innate and adaptive responses, immune evasion, and correlates of protection

• Development, optimization, and evaluation of in vivo models (mouse, rat, ferret, and other species), including translational relevance and prospects for controlled human infection models

• Novel in vitro models and organoid, microphysiological, or ex vivo systems for studying Y. pestis infection, transmission, and immune interactions

• Vaccine approaches and candidates in research, including subunit, recombinant protein, live-attenuated, viral vectored, DNA, and RNA platforms (e.g., saRNA; RNA vaccines expressing YscF/F1/V; heterologous prime–boost regimens)

• Combination and multivalent vaccine strategies, such as plague–melioidosis vaccines or formulations targeting multiple high-risk pathogens

• Therapeutic innovations, including humanized monoclonal antibodies, nanobodies, in situ induction of antibodies, phage therapies, novel antibiotics, and advanced adjuvants or immunomodulators

• Pre exposure and post exposure prophylaxis strategies against plague, including integration with vaccination, chemoprophylaxis, and antibody-based interventions

• Application of artificial intelligence, machine learning, and computational pipelines (e.g., RAPTOR and related programs) to antigen discovery, epitope mapping, drug repurposing, and optimization of plague vaccines and therapies

• Late-stage clinical candidates, WHO Target Product Profile–aligned products, and analyses of regulatory pathways, prospects for approval or emergency use authorization, and requirements for deployment in endemic, outbreak, and biodefense settings

Are you interested in contributing a manuscript to this Research Topic?

Evolution of Vaccines and Therapies for Plague: From Past Challenges to Future Insights