Leveraging immunostimulatory pathways that enhance BCG vaccination for the rational design of synthetic neonatal vaccine formulations

Inadequate stimulation of the neonatal immune system and the requirement for multiple booster administrations have limited the efficacy of the majority of current vaccine formulations. The former issue presents a window of vulnerability during which neonates and infants are highly susceptible to infection, resulting in over 2 million deaths worldwide each year. For the latter issue, patient noncompliance with returning to points of care for necessary boosters limits the penetration of vaccines within communities. Despite numerous shortcomings, including waning protection following childhood and ineffectiveness for adults, the Bacille Calmette-Guerin (BCG) attenuated vaccine against Mycobacterium tuberculosis (Mtb) safely elicits Th1 neonatal immune responses and requires only a single administration at the time of birth. Thus, although BCG is in dire need of improvement, it is not burdened by several critical deficiencies effecting most currently administered immunizations. Furthermore, patients immunized with BCG and other attenuated vaccines have demonstrated enhanced and more effective immune responses upon infection with unrelated pathogens later in life resulting lowered overall mortality. These off-target nonspecific benefits are often referred to as “heterologous” effects and suggest that immunostimulation by BCG and other attenuated vaccines may program neonatal immune cells for lasting immunological advantages. Thus there is a critical need to improve the majority of current vaccine formulations to achieve one-shot neonatal immunization while ensuring programming of neonatal immunity for retention of heterologous effects of attenuated vaccines. Furthermore, the current global shortage in BCG calls attention to the current lack of scalable synthetic formulations that can achieve similar and potentially improved efficacy relative to immunization with live attenuated pathogens. Achieving this goal will require a highly customizable, cost effective synthetic vaccine platform. We have identified the principle immunological responses elicited by the BCG vaccine and used these findings to rationally design a synthetic nanocarrier formulation to mimic and improve upon BCG-induced immunostimulation. These findings suggest that the complex immune responses generated by attenuated vaccines can be accurately mimicked synthetically, allowing extensive customization, optimization and rapid scalable production of subunit vaccine formulations that would otherwise not be possible. This proposal aims to build upon our recent success in neonatal immunization by achieving the following objectives: • Determine the effects of the IL-12p70/IFN-γ axis on Th1 polarized immunity and immunological memory in a neonatal immunization setting. • Develop a synthetic platform to support vaccination against diverse pathogens at birth by mimicking the molecular composition and release kinetics of BCG. • Identify, modulate, and tune beneficial heterologous effects of BCG vaccination and BCG-mimetic nanocarriers.