cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model

Abstract

Current strategies for improving protective response to influenza vaccines during immunosenescence do not adequately protect individuals over 65 years of age. Here, we used an aged mouse model to investigate the potential of co-delivery of influenza vaccine with the recently identified combination of a saponin adjuvant Quil-A and an activator of the STING pathway, 2’3 cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) via dissolving microneedle patches (MNPs) applied to skin. We demonstrate that synergy between the two adjuvant components is observed after their incorporation with H1N1 vaccine into MNPs as revealed by analysis of the immune responses in adult mice. Aged 21-month-old mice were found to be completely protected against live influenza challenge after vaccination with the MNPs adjuvanted with the Quil-A/cGAMP combination (5 µg each) and demonstrated significantly reduced morbidity compared to the observed responses in these mice vaccinated with unadjuvanted MNPs. Analysis of the lung lysates of the surviving aged mice post challenge revealed the lowest level of residual inflammation in the adjuvanted groups. We conclude that combining influenza vaccine with a STING pathway activator and saponin-based adjuvant in MNPs is a novel option for skin vaccination of the immunosenescent population, which is at high risk for influenza.

cGAMP-adjuvanted multivalent influenza mRNA vaccines induce broadly protective immunity through cutaneous vaccination in mice

“…cGAMP has been applied alone or in combination with other molecular adjuvants in multiple vaccine studies in recent years. 18 , 50 , 51 Previous studies have detailed how cGAMP stimulates the STING-initiated downstream type I interferon signaling pathway and induces cytokine expression. The innate signaling features of cGAMP give it potential as a safe and promising adjuvant candidate.…”

“…cGAMP is a natural STING agonist with a negative charge and has been demonstrated as an effective adjuvant for influenza vaccines. 17 , 18 αGC is a potential mucosal adjuvant capable of inducing mucosal secretory IgA (sIgA) and systemic IgG responses against viral infections. 19 , 20 , 21 Nanoplatforms incorporating αGC activated iNKT cells and generated augmented antigen-specific CTL responses.…”

Potentials of saponins-based adjuvants for nasal vaccines

“…Another example is the combination of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) and saponins, which improved protective response to influenza. Saponins can increase the permeability of cell membrane, allowing more cGAMP to enter the cells and increasing the utilization rate of saponins, leading to stronger immune effects ( 130 , 131 ). Furthermore, nasal delivery systems such as microspheres or nanospheres made of chitosan, PLGA (poly[D,L-lactic-co-glycolic acid]), alginate, or cross-linked dextran have been employed to encapsulate saponins for nasal administration ( 132 – 135 ).…”

The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development

“…However, whether CDNs can effectively enhance specific immune responses in aged or newborns remains to be determined [ 131 , 136 ]. Borriello et al found that although cGAMP induced a comparable expression of surface maturation markers in newborn and adult BMDCs, cGAMP adjuvantation alone failed to increase HA-specific antibody responses in newborn mice [ 136 ].…”