Yersinia pestis, the notorious agent behind bubonic and pneumonic plague, has shaped the course of human history with recurrent epidemics and catastrophic pandemics. Decades of research have unraveled much of its pathogenic arsenal, from its ability to evade the immune system to its molecular mechanisms for rapid transmission. Since the 1950s, scientific understanding of Y. pestis—supported by advances in genomics, structural biology, and immunology—has spurred the global quest for an effective, safe, and widely deployable vaccine. Entering the first quarter of the 21st century, researchers are now leveraging state-of-the-art biotechnologies to surmount previous obstacles, paving the way for innovative vaccines and therapies that can curtail outbreaks and mitigate future risks.

This article collection showcases breakthroughs in the evolution of plague vaccines and therapeutic strategies, with a particular emphasis on technological innovations such as recombinant protein platforms, self-amplifying RNA (saRNA), and advanced nanoparticle delivery systems. The collection traces the historical trajectory from early whole-cell vaccines to next-generation candidates, underscoring how modern insights into host–pathogen interactions, immune evasion, and genetic diversity are shaping more refined interventions. Special attention is given to combination approaches—like depot-formulated cytokines and adjuvants—that may enhance immunogenicity and provide durable protection in both endemic and outbreak scenarios. By critically examining the scientific progress and emerging challenges such as antimicrobial resistance, this collection seeks to inform researchers about this continued global public health threat.

To gather further insights into the evolution of Y. pestis vaccines and therapeutics, we welcome articles addressing, but not limited to, the following themes:

• Historical overview and milestones in Yersinia pestis vaccine development

• Structure-function analyses of Y. pestis virulence factors informing vaccine design

• Advances in subunit and recombinant protein plague vaccines

• Development and evaluation of self-amplifying RNA (saRNA) vaccines against Y. pestis

• Nanoparticle and lipid-based delivery systems for plague immunization

• Novel adjuvant and depot-formulation strategies to boost vaccine efficacy

• Insights from animal models

• Host-pathogen interactions and immune evasion mechanisms shaping vaccine strategies

• Updates on therapeutic antibody and small molecule development for plague treatment

• Combating antimicrobial resistance in Y. pestis: implications for therapy and vaccine design

• Future directions: personalized vaccines and real-time outbreak response platforms

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