Novel Mixed QS-21 Polymeric Micelles: A Breakthrough in Vaccine Delivery Systems

PATRICIO G. MÁRQUEZ; LEONARDO GABRIEL ALONSO; JUAN IGNACIO MARFIA; IGNACIO SMITH; CAROLINA MOURRELLE; MARÍA VICTORIA MIRANDA; SILVINA NOEMÍ VALDEZ; FEDERICO JAVIER WOLMAN; ROMINA J. GLISONI

CABA

Congreso; VII Congreso en Medicina Traslacional; 2024

International Master Program in Biomedical Sciences, Universidad de Buenos Aires, University of Freiburg

QS-21, a saponin fraction from Quillaja saponaria, is a potent immunostimulant employed in FDA- and EMA-approved vaccines for herpes zoster, malaria, and respiratory syncytial virus (RSV) disease. Besides, QS-21 is actively explored for melanoma, tuberculosis, and HIV/AIDS, among other diseases. However, QS-21 in its pristine form presents challenges, such as severe hemolytic activity (95-100% hemolysis) and self-aggregation in aqueous media. In addition, current liposome-based adjuvants delivering QS-21, such as AS01, represent high production costs. These issues limit its broader applications, highlighting the need for innovative solutions.Our goal was to develop a new nanoplatform based on mixed QS-21 polymeric micelles (mixed QS-21 PMs), offering an advanced alternative to liposome-based QS-21 formulations. The mixed QS-21 PMs was prepared by hydrating its components in PBS at 4°C overnight, and critical assembly parameters were determined using dynamic light scattering (DLS). This platform exhibited several key advantages, such as reduced hemolytic effects and enhanced immunostimulant properties. While pristine QS-21 induces nearly 100% hemolysis, our mixed QS-21 PMs showed a reduced hemolytic activity. Moreover, our pristine PMs exhibited less than 4% hemolysis, marking a significant improvement in safety. On the other hand, in rat immunization trials with the recombinant SARS-CoV-2 Spike protein, our formulation generated higher serum anti-Spike antibody titers than traditional formulations. Broncho-alveolar lavage samples showed elevated Positivity Index (PI), and antibodies produced in vivo were capable of virus neutralization, confirming the efficacy of our formulation. The mixed QS-21 PMs self-assembled into stable and monodisperse micelles above their critical micelle concentration (CMC), improving adjuvant delivery and stability. Lyophilization was also feasible, further enhancing stability for long-term storage, and enabling single-vial presentations. Our novel mixed QS-21 PMs demonstrated significantly reduced hemolytic activity and enhanced immunostimulant properties compared to pristine QS-21, making them a promising candidate for future vaccine formulations. To maximize the potential of this nanoplatform, we will optimize and scale-up the formulation, explore other antigens, and test additional disease models. Lyophilization can improve stability, facilitating clinical trials and commercialization. This platform represents a significant innovation in vaccine adjuvants, offering safer, more effective, and versatile solutions for a variety of immunotherapeutic applications.