Rodent control to fight plague : field assessment of methods based on rat density reduction

Research funding: Directorate General for International Relations and Strategy. Grant Number: 2018‐SB‐024‐18SSEOC049‐PMG7‐SSA5‐IPMMADAGASCAR ACKNOWLEDGMENTS: We are especially grateful to the health authorities and the population in Miantso and Ankazobe for allowing us to do this work and being so helpful. We thank the staff of the Plague Unit, Institut Pasteur de Madagascar, for helping with the field and laboratory work, especially Alain Berthin Rakotoarisoa and Andrianiaina Parfait Rakotonindrainy. This work was supported by a Directorate General for International Relations and Strategy grant (2018‐SB‐024‐18SSEOC049‐PMG7‐SSA5‐IPMMADAGASCAR) covering the project “Développement de contre‐mesures médicales à la peste à Madagascar” with scientific support of IRBA (French Armed Forces Biomedical Research Institute), within the framework of French MoD's involvement in G7 Global partnership. The French Agency for International Technical Expertise (AFETI) ensures the proper financial execution of the project and contributes to the implementation of cooperation actions under the control of the Directorate General for International Relations and Strategy. This research was also funded in part by the Wellcome Trust [095171/Z/10/Z] and the Institut Pasteur de Madagascar. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. K.S. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) under the EastBio DTP (grant number BB/M010996/1).Peer reviewedPublisher PD

A self-amplifying RNA vaccine provides protection in a murine model of bubonic plague

Mice were immunized with a combination of self-amplifying (sa) RNA constructs for the F1 and V antigens of Yersinia pestis at a dose level of 1 μg or 5 μg or with the respective protein sub-units as a reference vaccine. The immunization of outbred OF1 mice on day 0 and day 28 with the lowest dose used (1 μg) of each of the saRNA constructs in lipid nanoparticles protected 5/7 mice against subsequent sub-cutaneous challenge on day 56 with 180 cfu (2.8 MLD) of a 2021 clinical isolate of Y. pestis termed 10-21/S whilst 5/7 mice were protected against 1800cfu (28MLD) of the same bacteria on day 56. By comparison, only 1/8 or 1/7 negative control mice immunized with 10 μg of irrelevant haemagglutin RNA in lipid nanoparticles (LNP) survived the challenge with 2.8 MLD or 28 MLD Y. pestis 10-21/S, respectively. BALB/c mice were also immunized with the same saRNA constructs and responded with the secretion of specific IgG to F1 and V, neutralizing antibodies for the V antigen and developed a recall response to both F1 and V. These data represent the first report of an RNA vaccine approach using self-amplifying technology and encoding both of the essential virulence antigens, providing efficacy against Y. pestis. This saRNA vaccine for plague has the potential for further development, particularly since its amplifying nature can induce immunity with less boosting. It is also amenable to rapid manufacture with simpler downstream processing than protein sub-units, enabling rapid deployment and surge manufacture during disease outbreaks

Phylogenetic analysis of the origin and spread of plague in Madagascar

Background Plague is a zoonotic disease caused by the bacterium Yersinia pestis, highly prevalent in the Central Highlands, a mountainous region in the center of Madagascar. After a plague-free period of over 60 years in the northwestern coast city of Mahajanga, the disease reappeared in 1991 and caused several outbreaks until 1999. Previous research indicates that the disease was reintroduced to the city of Mahajanga from the Central Highlands instead of reemerging from a local reservoir. However, it is not clear how many reintroductions occurred and when they took place. Methodology/Principal findings In this study we applied a Bayesian phylogeographic model to detect and date migrations of Y. pestis between the two locations that could be linked to the re-emergence of plague in Mahajanga. Genome sequences of 300 Y. pestis strains sampled between 1964 and 2012 were analyzed. Four migrations from the Central Highlands to Mahajanga were detected. Two resulted in persistent transmission in humans, one was responsible for most of the human cases recorded between 1995 and 1999, while the other produced plague cases in 1991 and 1992. We dated the emergence of the Y. pestis sub-branch 1.ORI3, which is only present in Madagascar and Turkey, to the beginning of the 20th century, using a Bayesian molecular dating analysis. The split between 1.ORI3 and its ancestor lineage 1.ORI2 was dated to the second half of the 19th century. Conclusions/Significance Our results indicate that two independent migrations from the Central Highlands caused the plague outbreaks in Mahajanga during the 1990s, with both introductions occurring during the early 1980s. They happened over a decade before the detection of human cases, thus the pathogen likely survived in wild reservoirs until the spillover to humans was possible. This study demonstrates the value of Bayesian phylogenetics in elucidating the re-emergence of infectious diseases