OUSD (R&E) CRITICAL TECHNOLOGY AREA(S): Military Infectious Disease OBJECTIVE: Production of a vehicle for the sustained release of a human immunodeficient virus (HIV) vaccine for long-lasting antigen expression in large animal models of HIV infection and a prototype for human use. Production of this dual-use product for military and civilian use will lead to increased military medical readiness resulting in more efficacious vaccine products to protect the warfighter in large scale combat operations (LSCO) as well as in garrison. DESCRIPTION: U.S. military personnel are exposed to and impacted by the diverse global HIV epidemic. Despite advances in non-vaccine prevention, the US military experiences a steady epidemic of approximately 350 new HIV infections every year. Effective prevention and therapeutic modalities are of utmost importance in combatting HIV/AIDS in the DoD. The US Military HIV Research Program (MHRP) is engaged in collaborative research with multiple academic, corporate, and governmental partnerships to develop and test immunologic approaches to prevention and therapy. Conventional immunization strategies involve the delivery of vaccines in a bolus or a series of bolus injections. Natural exposure to HIV and other infectious diseases, however, result in the exposure of increasing levels of antigens and inflammation over days to weeks. Animal studies in mice have shown that the administration of HIV antigen and adjuvant over a 1-to-2-week period through repeated injections or using osmotic pumps resulted in 10-fold increases in antibody production compared to a bolus vaccination post prime. In another study, solid pyramidal microneedle (MN) arrays were implanted in the epidermis of mice and released HIV antigens over a 2-week period. Results from the study showed an approximately 1,300-fold increase of serum IgG titers, higher germinal center (GC) B cell responses, and a 16-fold increase in bone marrow (BM) plasma cells when compared to bolus immunization. While these studies have demonstration that vaccine kinetics and the timing of antigen and adjuvant delivery impacts immune responses to subunit vaccines, platforms to control the release or exact vaccine kinetics are not currently sufficient. The development of technology to support the sustained release of an HIV vaccine candidate is the desired end-state of this effort. The development of this technology would not only apply to the field of HIV, but also be applicable to other vaccines as well. PHASE I: Phase I consists of the development of a proof-of-concept vehicle that demonstrates scientific, technical, commercial merit and feasibility of a platform technology that relies on sustained antigen delivery for a successful HIV vaccine. The proof-of concept should demonstrate proof of feasibility of the vehicle in vitro by demonstrating the ease of use and the sustained release of stable antigen with a favorable antigenicity profile. Research could be built upon similar existing technology for other products such as sustained release hydrogels, sustained release silica microparticles, or pulsatile-release PLGA microspheres. Phase I will focus on technology conceptualization of sustained release vaccine technology (including performance parameters) and initial in vitro demonstration. The performer will design a sustained, timed release platform technology for the administration of an HIV vaccine. These methods may include the administration of vaccine via an intramuscular or subcutaneous injection, implantable device, or biomaterial that does not require removal. The platform should have the potential to deliver antigen over a minimum of a 2-week period, preferably in escalating dose. Upon completion of Phase I, a vehicle for sustained vaccine delivery will have been developed and undergone in vitro testing. PHASE II: After successful completion of Phase I, the focus is on optimizing and further development of the technology of at least one suitable deliverable developed in Phase I in a relevant small animal model (e.g., mice, rabbits or guinea pigs) as well as developing a prototype for clinical delivery. As described in Phase I, administration of the vaccine may be via an intramuscular or subcutaneous injection, implantable device, or biomaterial that does not require removal. The device or platform must not be large enough to inhibit movement or compromise Soldiers in an austere environment. A suitable prototype having already demonstrated to be suitable for use for further development as described in Phase I, will be further developed, evaluated, and optimized in a small animal model relevant to evaluating antibody responses to HIV vaccination. Initial efficacy and safety studies will be conducted in vivo. Studies should be conducted to demonstrate proof-of-concept that improved levels of serum IgG binding antibody titers, virus neutralization potency and breadth, and germinal center (GC) B cell responses can be achieved in animal models using this technology to deliver sustained release HIV antigens. A delivery prototype designed for the administration of a sustained release HIV vaccine in clinical settings will be developed and tested. The prototype specifications will be defined based on feedback from animal data to meet the requirements of the delivery system in humans. The expected Phase II end-state is a qualified, delivery modality to administer HIV vaccines using a sustained release platform technology. Enough of the deliverable should be produced to complete the objectives and testing as described in Phase III. Upon completion of Phase II of this project, the following will be completed: (1) Have developed a prototype for delivery of the sustained release HIV vaccine technology. (2) Have demonstrated immunogenicity of sustained release HIV vaccine technology in a small animal model relevant to HIV vaccine antibody responses. (3) A prototype product for the sustained delivery of an HIV vaccine for subsequent use in large animal models. (4) A strategy on how on how regulatory/FDA approval will be obtained for the product. PHASE III DUAL USE APPLICATIONS: In Phase III, the provider may continue, derive, or conclude the research conducted in the Phase II including testing validation in non-human primates (NHPs). Funding from non-SBIR/STTR government sources and/or the private/civilian sector will need to be obtained to develop or transition the prototype into a viable FDA-regulated product or service for clinical testing and subsequent deployment in military populations as well as commercialization and application in the civilian sector, domestically and even internationally. For example, funding could be obtained from the civilian or government sectors. Government sources of funding could include funding pathways via the Defense Health Agency (DHA) Pharmaceuticals, Devices, and Medical Support Systems (PDMSS), DHA Product Managers, and the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) Medical. A data package plan will also be required for application to the FDA after successful large field testing of the assay prototype. For HIV applications, the technology and/or product generated from the Phase III SBIR could be integrated in MHRP's objective of developing an HIV vaccine for the prevention of HIV/AIDS in support of the Infectious Disease Program Objective Memorandum (POM) to the HIV program in the 6.2 and 6.3 space. A potential method of transition for this product could be through the Army Futures Command. In addition, civilian commercialization of this product is likely to include GLP production and GMP manufacture and distribution. The end-state for this product is a commercially viable, FDA approved technology that will be commercially viable in the civilian sector, but also will support the Army's strategy of developing countermeasures against HIV/AIDS as well as global health applications for the deployment of an effective HIV vaccine. It may also be utilized as platform for the delivery of other vaccines and, thus, would benefit the field of vaccine development beyond HIV applications for both military and broader civilian populations. REFERENCES: 1. Boopathy A.V. et al. Enhancing humoral immunity via sustained-release implantable microneedle patch vaccination. Proc. Natl Acad Sci. USA 116, 16473-16478 (2019). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697788/ 2. Tam, H. H. et al. Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc. Natl Acad. Sci. USA 113, E6639 E6648 (2016). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5086995/ 3. Cirelli, K. M. et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell 177, 1153 1171 (2019). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619430 KEYWORDS: Human Immunodeficiency Virus; Autoimmune diseases syndrome; vaccine; therapeutics; antibodies; antigen; delivery; sustained release
