A Novel Self-Adjuvanting cc Particle-Based Tuberculosis Vaccine
Abstract
This application addresses Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area Tuberculosis. Mycobacterium tuberculosis (Mtb), the causative agent of the disease tuberculosis, remains a major public health threat worldwide. Mtb is reported by the World Health Organization to cause worldwide an estimated 10 million infections and 1.6 million deaths annually. Treatment regimens remain complicated, involving multiple drugs, which must be administered for prolonged periods of time. While vaccines have historically been among the most effective means of reducing morbidity and mortality from infectious diseases and despite substantial effort, effective Mtb vaccines remain elusive. Antigens, targets of the immune response, such as the Mtb proteins ESAT6 and Ag85B have been demonstrated to have promise as the basis of vaccines. However, developing effective immune responses to these antigens requires co-administration of immune boosters known as adjuvants. Further, the choice of adjuvant appears to impact the efficacy of vaccination. The need to optimize both a vaccine and to pair it with an appropriate adjuvant complicates vaccine development. Further, the need for an appropriate adjuvant suggests that the specific immune pathways activated by the adjuvant are important to the effectiveness of the Mtb vaccine. Another limitation of many current approaches to Mtb vaccines is that multiple immunizations are needed to induce a strong immune response to the vaccine. Requiring individuals to be present to medical personnel multiple times over the course of several months would greatly hamper effective vaccination of populations. This proposal seeks to develop a unique vaccine that has several advantages over existing Mtb vaccine candidates. The vaccine takes a virus-like particle approach. Virus-like particles are produced by virus-derived proteins but are safe because they do not contain any virus genes and cannot propagate. The virus-like particles of the proposed vaccine are from Ebola virus and includes the viral glycoprotein (GP), the viral matrix protein known as VP40 and part of the virus nucleoprotein (NP). This system was chosen because the components are well-defined. This allowed introduction into the virus-like particles of a portion of NP fused to part of a cellular protein, referred to as 2CARD, that is a strong immune stimulator. Introduction of 2CARD into the virus-like particles greatly boosts immune responses to the particles, thereby providing a strong adjuvant effect. A further advantage of the Ebola virus-like particle approach is that GP directs the particles to antigen presenting cells, which are designed to stimulate immune responses. It is hypothesized that by providing a strong adjuvant effect and delivering particles to the appropriate cell types provides a platform upon which a more effective Mtb vaccine can be built. Therefore, this proposal will build two Mtb antigen proteins, ESTA6 and Ag85B, into the Ebola virus-like particle system and test this approach for its capacity to improve upon existing Mtb vaccine approaches. Successful completion of the proposed studies will pave the way for further development of this approach as an Mtb vaccine and suggest that the approach should be applied to other important human pathogens.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010099
Entities
People
- Joann Tufariello
Organizations
- Georgia State University
- United States Army