Rapidly Applicable, Flexible Vaccine Technologies for Bacterial Pathogens
Abstract
Development of each new vaccine against a disease-causing bacteria is a long process involving decades of effort to identify either (1) a weakened (attenuated) form of the live bacterium or (2) a bacterial component (an antigen-Ag) capable of generating protective immunity. Furthermore, to be useful as vaccines, these strategies must be able to provoke a protective immune response without causing disease. Stimulating a potent immune response usually involves the use of additives (adjuvants) that can have unwanted side effects due to their broad activity. As such, there is a pressing need for novel, adjuvant-independent vaccine technologies that can be rapidly applied (“Plug-and-Play”) to multiple types of bacteria without decades of knowledge specific to each bacterium. Our proposal, “ Rapidly Applicable, Flexible Vaccine Technologies for Bacterial Pathogens” addresses these concerns and is directly responsive to the Topic Area “Vaccine Development for Infectious Diseases” and the Area of Encouragement “Flexible Technologies to Rapidly Respond to Emerging Diseases”. Adjuvant-Independent: Our approach does not rely upon adjuvants but instead uses engineered components of our innate immune system to target vaccine bacteria (live or killed) specifically for delivery to the “first-responder” immune cells that initiate formation of protective immunity. Also unlike traditionally added adjuvants, which have off-target toxicity/reactogenicity concerns, our targeting moieties are attached to the vaccine bacterium - focusing the immune stimulatory effect on the immune cell that is engaging the bacterium. Rapidly and Widely Deployable: Since our technologies rely on rudimentary mechanisms of biochemistry, our approaches are applicable to bacteria other than Francisella tularensis (Ft, a gram-negative, intracellular bioterrorism concern, and a primary focus of this proposal). We have preliminary data indicating that our targeting moieties (with no further modification) also function with Streptococcus pneumoniae (a gram-positive, extracellular cause of secondary bacterial pneumonia) and Klebsiella pneumoniae (a gram-negative of grave concern to Centers for Disease Control and Prevention [CDC] and World Health Organization [WHO] as a near-totally drug-resistant pathogen). Accordingly, success in the near term with Ft will provide a roadmap for applying this approach to other pathogens and change the paradigm for vaccine development – even for newly emergent bacteria for which we do not/will not have decades of knowledge. We have developed two independent technologies for targeting whole bacteria (killed or live, attenuated) to proteins (receptors) on antigen presenting cells (APC). Each approach targets a distinct receptor (the antibody Fc receptor - FcR, or the complement receptor - CR), and both technologies improve vaccine efficacy. Our first technology is a purified fusion protein (FP) that can be added directly to live or inactivated bacteria to target the resulting immunogen to human Fc receptor gamma (FcgammaRI) on APCs. This patent-pending FP is a chimera of (i) mannose-binding lectin 2 (a component of our innate immune which binds to sugar moieties on the surfaces of most bacteria) and (ii) the variable domain of a monoclonal antibody (mAb), which binds human FcgammaRI outside of the Fc-binding cleft. Our second technology is a plasmid that targets transformed bacteria (live or inactivated) to complement receptors (CR) on APCs. Our patented, first-generation plasmid achieved this targeting through fusion of C3d (a ligand for CR2 and 3) to a Francisella-specific, outer membrane protein (OMP). To move this technology beyond Francisella, we have developed platforms based on broadly conserved, bacterial autotransporters (AT) fused to C3d or p28, the minimal CR-ligand. Our long-term objective is to develop these rapidly applicable technologies for broad utility with multiple pathogens. The immediate goals of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910662
Entities
People
- Edmund Gosselin
Organizations
- Albany Medical College
- United States Army