Adenovirus vector and mRNA vaccines: Mechanisms regulating their immunogenicity

Abstract

Replication-incompetent adenovirus (Ad) vector and mRNA-lipid nanoparticle (LNP) constructs represent two modular vaccine platforms that have attracted substantial interest over the past two decades. Due to the COVID-19 pandemic and the rapid development of multiple successful vaccines based on these technologies, there is now clear real-world evidence of the utility and efficacy of these platforms. Considerable optimization and refinement efforts underpin the successful application of these technologies. Despite this, our understanding of the specific pathways and processes engaged by these vaccines to stimulate the immune response remains incomplete. This review will synthesize our current knowledge of the specific mechanisms by which CD8⁺ T cell and antibody responses are induced by each of these vaccine platforms, and how this can be impacted by specific vaccine construction techniques. Key gaps in our knowledge are also highlighted, which can hopefully focus future studies.

Keywords: COVID-19; adenovirus vector; cellular memory; innate response; mRNA vaccines.

Figure 1

Pathways known to promote or inhibit the induction of cellular and humoral immune responses following adenovirus vector immunization. Key pathways and immune processes identified by mouse studies are shown in solid lines. Black arrows denote processes shown to promote immune responses, while red lines denote inhibition. Dashed lines indicate where correlative data in humans or non‐human primates suggests an interaction between cell types. Where cells have been shown to interact, but molecular mechanisms have not been determined, this is noted. Not all pathways have been examined for all different major serotypes of Ad vectors, so the presented model is a synthesis of studies using the different vectors. Known cases of vector‐specific differences are noted in the model. See text for references for indicated pathways.

Figure 2

Pathways known to promote or inhibit the induction of cellular and humoral immune responses following mRNA vaccine immunization. Key pathways and immune processes identified by mouse studies are shown in solid lines. Black arrows denote processes shown to promote immune responses, while red lines denote inhibition. Dashed lines indicate where correlative data in humans or non‐human primates suggests an interaction between cell types or the mouse studies have identified a cytokine as important but the exact producer and target cell are unknown. Where cells have been shown to interact, but molecular mechanisms have not been determined, this is noted. Not all pathways have been examined for all different types of mRNA vaccines. The presented model is focused on data specifically in the context of nucleoside‐modified mRNA vaccines, except where specifically noted. See text for references for indicated pathways.