Improving the therapeutic efficacy of a lead vaccine against plague using a novel adjuvant system

DESCRIPTION provided by applicant FasCure Therapeutics focuses on the development of adjuvant systems to generate prophylactic and therapeutic immune responses The major objective of this Phase STTR proposal is to reformulate a lead plague subunit vaccine with a novel adjuvant system to improve its protective efficacy Yersinia pestis is the causative agent of bubonic and pneumonic plague and a potential bioweapon Currently there is not a vaccine available to protect the public from a potential epidemic or bioterrorism event While Y pestis infection can be treated with antibiotics the effective treatment window for primary pneumonic infection is very short less than hrs after exposure Furthermore naturally acquired resistance to antibiotics has been reported and weaponized Y pestis could likely be modified to be resistant to antibiotic treatment Therefore the development of an efficacious plague vaccine is an important scientific endeavor and public policy goal The current lead vaccine against plague is a subunit vaccine formulation consisting of a recombinant F LcrV fusion protein rF V adjuvanted with alum This vaccine has proven effective in rodent models but has decreased efficacy in primate models and variable antibody production in clinical trials Therefore while rF V appears to be an excellent vaccine candidate for plague it needs further improvement to produce a better immunogenicity profile While the current vaccine primarily generates a Th humoral immune response several studies have demonstrated a critical role of Th cellular responses in protection against plague Therefore the primary focus of this proposal is to establish a novel adjuvant system that generate a mixed Th and Th immune responses and use adjuvant to improve the efficacy of lead rF V vaccine This goal will be achieved by using alum MPL and SA BBL as agonists NLRs TLR and the BB receptor respectively that are critical for the generation of effective Th cellular and Th humoral immune responses Aim will establish the optimum dose of each adjuvant to generate balanced robust Th and Th responses against the rF V antigen Aim will use the lead vaccine formulation to determine its protective efficacy against pneumonic plague in mice If successful a Phase II proposal will be submitted to further develop this vaccine formulation by testing its protective efficacy against
plague using a nonhuman primate model as a prelude to clinical trials Importantly the proposed adjuvant system may also be used as a platform to generate new subunit vaccines or improve the efficacy of the existing ones against other intracellular pathogens that need a balanced immune response

PUBLIC HEALTH RELEVANCE No vaccine for plague is available in the US to protect the public from a future epidemic or bioterrorism attack The main objective of this proposal is to fas track the development of the existing lead plague vaccine candidate by using a novel adjuvant system to improve efficacy These studies will establish the vaccine formulation and characterize the role of different components of the immune system in vaccine protection these data will guide future tests in primate models and human clinical trials