Editorial: The World Health Organization (WHO) Updated List of Emerging and Potentially Pandemic Pathogens Includes Yersinia pestis as Plague Vaccines Await Clinical Trials

More than five years after the beginning of the COVID-19 pandemic, important lessons have been learned, and infection control initiatives have been developed to identify and prevent future pandemics from emerging and re-emerging infectious diseases [1]. The importance of rapid development and distribution of safe and effective vaccines was a major lesson learned from the COVID-19 pandemic, which drove new vaccine development technologies at an astonishing rate [2,3]. In 2023, the World Health Organization (WHO) developed the Preparedness and Resilience for Emerging Threats (PRET) initiative to improve disease pandemic preparedness by sharing data on modes of infectious disease transmission and prevention worldwide [4]. In May 2024, the WHO updated the identification of bacterial pathogens of importance to public health as guidance for research and development of strategies to prevent and overcome global antimicrobial resistance (AMR) [5]. In June 2024, the WHO updated the 2017–18 list of priority pathogens to provide a scientific framework for epidemic and pandemic preparedness (Table 1) [6,7]. The importance of regional disease surveillance has been highlighted, as shown by outbreaks of cholera, dengue, and Mpox in Africa, Oropouche virus and H5N2 avian influenza in North America and South America, and Nipah virus disease in Bangladesh [6,7]. The 2024 WHO recommendations not only list the priority pathogens but also highlight the need to improve global preparedness for upcoming pandemics through disease surveillance, identifying disease outbreaks and epidemics, and preparation of vaccines to prevent epidemics and pandemics [6,7]. The 2024 updated list of pathogens also recognizes not only emerging infections but also historical former pandemic infections, with the inclusion of Yersinia pestis, the cause of bubonic, pneumonic, and septicemic plague, as a key re-emerging pathogen (Table 1) [6,7].

Yersinia pestis is a gram-negative bacterium with zoonotic transmission [8]. Bubonic plague, due to infection with Yersinia pestis, has been identified as a human disease for more than 5,000 years [8]. The history of plague epidemics and pandemics has shown the devastating effects of this infection [9,10]. The Athenian plague occurred in 430 BC and killed up to 5 million (25%) Athenians before spreading through the Roman Empire [10]. The Antonine plague occurred during 165–180 AD, and the Black Death occurred between 1346–1353 AD [10]. The Antonine plague caused an estimated 5 million deaths [10]. The Mediterranean and European regions lost approximately 60% of their population due to the Black Death, or bubonic plague [11]. The plague caused an estimated 200 million deaths in the Middle Ages [9].

Archeological samples from Europe and Asia have identified Yersinia pestis genomes that suggest clonal evolution from the closely related enteric pathogen Yersinia pseudotuberculosis sometime around the Bronze Age [8]. The mutations allowed Yersinia pestis to transmit to ectoparasites (including fleas) while maintaining enteric transmissibility [8]. The first historic pandemic of plague began in 541 AD, with sporadic epidemics until now [8,9]. The reasons for the persistence of Yersinia pestis in the environment include the localized and low levels of the organism in contaminated soils, the varied degrees of susceptibility of burrowing and nonburrowing mammals to infection, and the transmission between hosts by fleas or by droplet inhalation from an infected animal [8]. An infected flea bite can result in typically enlarged and painful lymph nodes (the bubo), followed by blood-borne dissemination or septicemia [8,10]. After close contact with an infected mammal, droplet inhalation can result in primary pneumonic plague [8]. A rare cause of plague is consuming contaminated raw meat, which causes pharyngeal and gastrointestinal infections [8]. Early diagnosis and antibiotic treatment can control disease outbreaks, but only when methods of diagnosis and treatments are available [8]. Primary disease prevention relies on infection surveillance and control of human ectoparasites [8]. Outbreaks of zoonotic bubonic plague are reported mainly in African countries due to human transmission by flea bites from rodents [8].

Between 2010 and 2019, the six countries with the most reported human cases of Yersinia pestis infection (from highest to lowest) were Madagascar, the Congo, Uganda, Peru, Tanzania, and the USA, with a total of 4,547 cases and a mortality rate of 17% (786 cases) [12]. Between 2010 and 2019, four outbreaks of primary pneumonic plague occurred in Madagascar, affecting 1,936 people, with a mortality rate of 7% (137) cases [12]. Importantly, one of the outbreaks was caused by a streptomycin-resistant strain of Yersinia pestis, and cases of person-to-person transmission were identified [12]. Unique clinical presentations have been described in the USA, including from pet dogs to humans, septicemic plague associated with osteomyelitis and arthritis, and bubonic plague transmitted from the bite of a sick prairie dog [12]. The persistence of outbreaks of Yersinia pestis infection, the development of antibiotic resistance, and the changing modes of transmission and clinical presentation all indicate potential epidemic and pandemic disease and highlight the importance of urgently developing safe and effective vaccines [13].

Infection with Yersinia pestis is recognized as a threat to vulnerable populations, has the potential for global spread, and remains a potential biothreat without an approved vaccine [14]. Seasonal outbreaks in endemic areas, such as Madagascar, result in fatal cases, with the potential for climate change and changes in disease transmission, causing further cases and increased mortality [14]. Following lessons learned from the COVID-19 pandemic, the WHO has endorsed preventing vector-borne diseases by 2030 [3]. These goals recommended by the WHO are particularly relevant to preventing plague [4]. There have been decades of research to establish the key targets for vaccines for Yersinia pestis that can produce a cellular and humoral immune response [13]. Most studies have been preclinical and done in animal models. Although potential vaccine targets have been identified, there is insufficient data from randomized controlled trials of live, attenuated, or killed plague vaccines [13]. Therefore, further approaches to vaccine development to prevent plague are required, and lessons may be learned from vaccine development technologies used to develop vaccines for SARS-CoV-2 during the COVID-19 pandemic [13]. In 2023, the WHO published a draft target product profile (TPP) for a future plague vaccine, which identifies the qualifying criteria for a vaccine in terms of vaccine regimens, routes of vaccine administration, presentation, target efficacies, stability, and coverage, all of which would be applied to any plague vaccine candidate [4,14].

Currently, there are more than 20 candidate vaccines in the preclinical phase, but few in early (phase 1) clinical trials [14,15]. Plague vaccine candidates include subunit vaccines, live attenuated vaccines, vector (bacterial or viral) vaccines, DNA vaccines, or messenger RNA (mRNA) vaccines [14]. Vaccines directed to the F1 and V subunit antigens have provided a high degree of protection against infection caused by Yersinia pestis in several animal models [14]. Adjuvants used in preclinical recombinant combined F1V vaccine development studies include the toll-like receptor 5 (TLR5) ligand flagellin [14]. The live attenuated vaccine (LAV) strain EV76-NIIEG has been used for human vaccination in Russia and China for many years to prevent plague outbreaks [14]. Recombinant DNA technology has been used in vaccination development since the 1980s [14]. Attenuated bacterial or viral vectors can deliver shared antigens derived from Yersinia pestis, including Salmonella, Yersinia pseudotuberculosis, Lactobacillus, adenovirus, vesicular stomatitis virus, and vaccinia virus [14]. DNA-based plague vaccines comprising F1 and LcrV have also been tested and found to be immunogenic and protective in preclinical studies [14]. More recently, mRNA technology has been extended to produce candidate plague vaccines, and rapid advances in large-scale manufacturing for mRNA vaccines for SARS-CoV-2 could be transferred to the plague mRNA vaccines [14,15].

The Oxford Vaccine Group has developed a chimpanzee adenovirus vector (ChAdOX1) vaccine expressing F1 and V, using techniques to develop SARS-CoV-2 vaccines [4,16]. The ChAdOX1 vector is a replication-deficient adenoviral vector based on the simian adenovirus type Y25, chosen initially to avoid pre-existing adenovirus immunity in the human population [4,16]. The ChAdOx1 recombinant adenovirus-based plague vaccine (PlaVac) is now undergoing a phase I study to assess its safety and immunogenicity [4,16]. Currently, no approved and licensed vaccines against plague exist for global use [14]. The ChAdOx1 (PlaVac) plague vaccine has been developed to provide immune protection after just one dose [4,16].

Significant improvements in healthcare infrastructure are required to successfully implement vaccination programs to prevent plague, including developing specialized response units and upgrading laboratory facilities [17.18]. Investment in workforce training is equally important to equip healthcare professionals with the much-needed skills to utilize new detection methods and respond to emerging threats [17,18]. Global health authorities should create adaptable policies that quickly address evolving threats, such as the recent Preparedness and Resilience for Emerging Threats Initiative (PRET) by WHO for pandemic planning [4]. Strengthening healthcare infrastructure and expanding workforce training are essential for building resilient systems to withstand future pandemics [17]. Community engagement is also key, fostering public awareness and compliance with health measures during outbreaks of plague [18].

Conclusions

The inclusion of Yersinia pestis in the 2024 updated list of priority pathogens by the WHO has raised the profile of this ancient but re-emerging infection. The persistence of plague outbreaks, the development of antibiotic resistance, the changing modes of transmission of Yersinia pestis, and the changing clinical presentation all indicate a potential epidemic and pandemic disease. For all these reasons, there is an urgent need to develop safe and effective vaccines to prevent plague as part of pandemic preparedness.