The most serious outbreak of plague in modern times occurred in Madagascar in 2018, with in excess of 2600 cases and an estimated case fatality rate of 8.9% (WHO 2018). In Madagascar as well as in other parts of the world, plague causes seasonal outbreaks, with risk of epidemic potential and transmission to new regions. These seasonal outbreaks are caused by flea-vectored transmission from wildlife reservoirs (principally rats). There is no approved vaccine for plague and antibiotic therapy needs to be given early after exposure to infection, to be fully effective. Here we propose to test a sub-unit vaccine in a novel formulation for efficacy against a Malagasy strain of the causative bacterium, Yersinia pestis. In a previous liquid formulation, this sub-unit vaccine has been shown to be efficacious in mice and macaques against the reference Y.pestis Co92 type strain and was also shown to be safe and immunogenic in a Phase 1 clinical trial (Williamson et al 2005). Here, we have reformulated the vaccine for distribution to an LMIC, as a stable, dry powder which is reconstituted just before use. We will test the vaccine under laboratory conditions at the Institute Pasteur in Madagascar in rats derived from either plague-infected or non-infected areas of the island, prior to challenge with a circulating Malagasy strain of plague. The objective is to determine if this vaccine can induce immunity in the local rat population, preventing transmission to man. Production of a vaccine will mitigate development of AMR resistant strains of plague.
Candidate plague vaccine formulations were produced in the UK and tested at the Institut Pasteur of Madagascar. The novel dry powder formulations were shipped to Madagascar at room temperature and tested using Malagasy wild rats from plague endemic areas or from plague free areas. Vaccine formulations were prepared by incorporating protein antigens within calcium phosphate coated microcrystals (CaP-PCMC) and formulations containing either separate F1, V antigens or an F1-V fusion protein were tested.
The study showed that all of the formulations produced an immune response in rats specific to the F1 antigen, following subcutaneous delivery of the vaccine and this typically increased following boosting. Notable differences were observed with the rats from plague endemic areas producing a stronger immune response even where first generation laboratory bred rats were used. On day 57 the rats were challenged with a high dose of a Malagasy strain of plague (107 cfu). Protection against challenge was observed in most rats that showed a strong antibody titre. This is important as it indicates that the selected antigens are effective against a Malagasy strain of plague and also that the CaP-PCMC formulation allows for room-temperature shipment of the vaccine.
Notably it was also observed that a single dose of vaccine was sufficient to provide protection for formulations containing either the individual antigens or the F1-V fusion. Thus, there is a clear opportunity to use this approach in the development of an emergency LMIC vaccine and this study provided important information about the factors that will need to be considered when selecting a lead vaccine candidate to take forward for clinical development.
This work was a collaboration between DSTL (antigen production), University of Strathclyde (vaccine formulation) and the Institut Pasteur of Madagascar (vaccine study).
Dr Barry Moore
Reader of Biophysical Chemistry
Pure & Applied Chemistry, University of Strathclyde (UK)
Dr Minoarisoa Rajerison, Institut Pasteur Madagascar (Madagascar)
Dr Diane Williamson, DSTL (UK)