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Immunology of RNA-based vaccines: The critical interplay between inflammation and expression
John S Tregoning1, Ziyin Wang1, Saranya Sridhar2
1Department of Infectious Disease, Imperial, London SW7 2AZ, UK.
Abstract:
Since its use during the COVID-19 pandemic, mRNA has emerged as a leading candidate vaccine platform for pandemic infections. A critical difference between RNA-encoded antigen and protein vaccines is that RNA-based vaccines require the antigen to be translated in the body, adding an important variable. Much of the research focus in the field has been on ways to increase expression, but inflammation plays a critical role. The vaccine delivered is a combination of the RNA and the formulation, so both elements need to be considered. Formulated RNA can act as a form of adjuvant but can also activate cellular pathways that inhibit expression. Expression and inflammation are interlinked, but independent-a deeper understanding of the quality and quantity of immune induction will help to develop more efficient RNA vaccines. Here, we discuss factors that shape responses to RNA-based vaccines. These include the composition of the vaccine (the use of modified RNA bases, whether self-replicating or traditional mRNA and, critically, the formulation) and the type of cells that take up and translate the RNA. We then consider challenges presented by current generation RNA vaccines including clinical impact and how improved immunological understanding can inform the development of improved RNA vaccine platforms.
Insights
Messenger RNA (mRNA) vaccines are crucial for pandemic preparedness. Optimizing vaccine formulation and understanding immune responses are key to developing more effective mRNA vaccines against emerging infectious diseases.
Area of Science:
- Vaccinology
- Immunology
- Molecular Biology
Background:
- Messenger RNA (mRNA) vaccines have become a primary platform for addressing pandemic infections following their use during the COVID-19 pandemic.
- Unlike protein vaccines, RNA-based vaccines rely on in-body translation of the antigen, introducing a critical variable.
- Research has largely focused on enhancing expression, often overlooking the significant role of inflammation.
Purpose of the Study:
- To explore factors influencing immune responses to RNA-based vaccines.
- To discuss the interplay between RNA vaccine composition, formulation, and cellular interactions.
- To identify challenges in current RNA vaccine generations and propose improvements based on immunological understanding.
Main Methods:
- Review of existing literature on RNA vaccine technology and immunology.
- Analysis of vaccine composition, including modified RNA bases, mRNA type (self-replicating vs. traditional), and formulation.
- Consideration of cellular uptake and translation processes.
Main Results:
- Both RNA composition and formulation critically impact vaccine efficacy and immune response.
- Formulations can act as adjuvants but may also trigger inflammatory pathways that suppress expression.
- Expression and inflammation are interconnected but distinct factors influencing vaccine outcomes.
Conclusions:
- A comprehensive understanding of both expression and inflammation is vital for developing superior RNA vaccines.
- Factors such as modified RNA bases, mRNA type, and formulation significantly shape immune induction.
- Improved immunological insights are essential for overcoming challenges and advancing RNA vaccine platforms for future pandemics.
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