Polymeric cGAMP microparticles affect the immunogenicity of a broadly active influenza mRNA lipid nanoparticle...

Area of Science:

• Vaccinology
• Immunology
• Virology

Background:

• Annual influenza outbreaks pose a significant global health challenge.
• Seasonal influenza vaccines require yearly updates due to viral mutation.
• Messenger RNA (mRNA) encapsulated in lipid nanoparticles (LNPs) has emerged as a successful vaccine platform.

Purpose of the Study:

• To develop a broadly protective influenza vaccine using mRNA LNP technology.
• To evaluate the immunogenicity and protective efficacy of a computationally optimized broadly active (COBRA) influenza immunogen delivered via LNPs.
• To investigate the impact of a STING agonist adjuvant on the immunogenicity of COBRA mRNA LNPs.

Main Methods:

• Delivery of a COBRA influenza immunogen via lipid nanoparticles (LNPs).
• Combination therapy with acetalated dextran microparticles encapsulating a STING agonist.
• Assessment of neutralizing antibody response and protection against lethal influenza challenge.
• In vitro analysis of mRNA translation efficiency.

Main Results:

• COBRA mRNA LNPs successfully induced broadly active neutralizing antibodies.
• The COBRA mRNA LNPs provided protection against lethal influenza challenge.
• Co-administration with a STING agonist unexpectedly decreased the immunogenicity of the COBRA mRNA LNPs.
• In vitro studies suggested the STING agonist reduced mRNA translation.

Conclusions:

• mRNA LNPs are a promising platform for developing broadly protective influenza vaccines.
• The combination of COBRA mRNA LNPs with a STING agonist adjuvant was not beneficial and potentially detrimental.
• Further research is needed to understand adjuvant interactions with mRNA LNP vaccines to optimize future vaccine design.