Multi-COBRA hemagglutinin formulated with cGAMP microparticles elicit protective immune responses against influenza viruses

Xiaojian Zhang; Hua Shi; Dylan A Hendy; Eric M Bachelder; Kristy M Ainslie; Ted M Ross

doi:10.1101/2024.02.27.582355

Multi-COBRA hemagglutinin formulated with cGAMP microparticles elicit protective immune responses against influenza viruses

bioRxiv [Preprint]. 2024 Feb 29:2024.02.27.582355. doi: 10.1101/2024.02.27.582355.

Authors

Xiaojian Zhang¹, Hua Shi¹, Dylan A Hendy², Eric M Bachelder², Kristy M Ainslie^{2

3

4}, Ted M Ross^{1

5

6

7}

Affiliations

¹ Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA.
² Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA.
³ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA.
⁴ Department of Microbiology and Immunology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁵ Florida Research and Innovation Center, Port Saint, Cleveland Clinic Florida, Port St. Lucie, FL, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA.
⁶ Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL, USA.
⁷ Department of Infection Biology, Lehner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Abstract

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.

Keywords: COBRA; acetalated-dextran (Ace-DEX); cGAMP; influenza; mice; microparticles (MPs); vaccine.

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Abstract

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