Influenza viruses cause a common respiratory disease known as
influenza. In humans, seasonal influenza viruses can lead to epidemics, with
avian influenza viruses of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a
universal influenza vaccine that provides protection against seasonal and pre-pandemic influenza virus strains. The
cyclic GMP-AMP (
cGAMP) is a promising adjuvant for
subunit vaccines that promotes
type I interferons production through the stimulator of
interferon genes (
STING) pathway. The encapsulation of
cGAMP in acetalated
dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive
Antigen (COBRA) methodology was used to generate H1, H3, and H5
vaccine candidates. Monovalent and multivalent COBRA HA
vaccines formulated with
cGAMP Ace-DEX MPs were evaluated in a mouse model for antibody responses and protection against viral challenge. Serological analysis showed that
cGAMP MPs adjuvanted monovalent and multivalent COBRA
vaccines elicited robust
antigen-specific antibody responses after a prime-boost vaccination and antibody titers were further enhanced after second boost. Compared to COBRA
vaccine groups with no adjuvant or blank MPs, the
cGAMP MPs enhanced HAI antibody responses against COBRA vaccination. The HAI antibody titers were not significantly different between
cGAMP MPs adjuvanted monovalent and multivalent COBRA
vaccine groups for most of the viruses tested in panels. The
cGAMP MPs adjuvanted COBRA
vaccines groups had higher
antigen-specific
IgG2a binding titers than the COBRA
vaccine groups with no adjuvant or blank MPs. The COBRA
vaccines formulated with
cGAMP MPs mitigated disease caused by
influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA
vaccines plus
cGAMP MPs is a promising
universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.