Clinical development of a new vaccine for rapid response against Plague: GMP

This project aims to progress a novel vaccine against plague (Yersinia pestis), developed during a Innovate UK stream 1 project, to clinical development, including production of the vaccine in an approved facility for use in humans and a phase I clinical trial. The trial will determine the new vaccine’s safety in healthy adult volunteers, and also allow the quantification and characterization of its immunogenicity in humans. Our novel vaccine against plague uses a potent vaccine delivery technology suitable for outbreak situations in low-income countries. Plague is a highly contagious and virulent infectious disease: Since the 1990s, the number of human plague cases has increased in 25 countries, and plague is now classified as a re-emerging infectious disease for the following reasons: 1. there are large reservoirs in Africa, Asia and the Americas, 2. its endemicity throughout the world results in sporadic infections and outbreaks (including recent epidemic in the 21st century), 3. There is 100% mortality unless antibiotic treatment of pneumonic plague is commenced within 24 h after the onset of symptoms, 4. its potential use as a bioweapon due to its extreme virulence and ease of spread (through aerosol), and 5. the emergence of antibiotic-resistance strains. Vaccine development efforts against plague have been dominated by the use of live attenuated vaccines and sub-unit proteins. Live attenuated vaccines pose significant safety concerns and there is disagreement over the level of protection achieved. Sub-unit proteins in adjuvant have demonstrated a certain degree of protection in animal models, but the immune response seems limited to antibodies, while a cellular response correlates with increased efficacy. Our novel vaccine is based on a harmless replication-incompetent virus, usually responsible for upper respiratory tract infections, but rendered harmless by genetic modification. This vaccine technology is highly immunogenic, currently used for developing new vaccines against several infectious diseases such as Ebola, malaria, influenza, HIV, TB and capsular group B meningococcus. It is also suitable for diseases for which cellular immune responses are required for protection, in addition to antibody responses as is the case for plague. Moreover it is also suited to outbreak situation in low-income countries, as it induces rapid response after a single injection. For the recent Ebola outbreak, all vaccines evaluated in the field were based on viral vectors. We have created a vectored plague vaccine that expresses proteins known to elicit protective immune responses. We have demonstrated that a single dose vaccine induces the desired immune response, with levels matching the responses induced by two injections of a high-dose adjuvanted sub-unit protein-based vaccines. In this project, the vaccine will be produced to good manufacturing practice (GMP conditions), and will be tested in a first-in-man phase I clinical trial. Our group has expertise in progressing vectored based vaccines against bacterial pathogens to GMP production and phase I trial. We will assess the safety of the vaccine composition in healthy adult volunteers, investigate the immune responses induced in humans, measure the level of protection induced by the antibodies, and identify the optimal dose to be used in adults. If successful, this project will provide a strong case for progressing this new vaccine against plague in phase II development.