Nucleic acid vaccines: innovations, efficacy, and applications in at-risk populations

Abstract

For more than two centuries, the field of vaccine development has progressed through the adaptation of novel platforms in parallel with technological developments. Building off the advantages and shortcomings of first and second-generation vaccine platforms, the advent of third-generation nucleic acid vaccines has enabled new approaches to tackle emerging infectious diseases, cancers, and pathogens where vaccines remain unavailable. Unlike traditional vaccine platforms, nucleic acid vaccines offer several new advantages, including their lower cost and rapid production, which was widely demonstrated during the COVID-19 pandemic. Beyond production, DNA and mRNA vaccines can elicit unique and targeted responses through specialized design and delivery approaches. Considering the growth of nucleic acid vaccine research over the past two decades, the evaluation of their efficacy in at-risk populations is paramount for refining and improving vaccine design. Importantly, the aging population represents a significant portion of individuals highly susceptible to infection and disease. This review seeks to outline the major impairments in vaccine-induced responses due to aging that may be targeted for improvement with design and delivery components encompassing mRNA and DNA vaccine formulations. Results of pre-clinical and clinical applications of these vaccines in aged animal models and humans will also be evaluated to outline current successes and limitations observed in these platforms.

Keywords: DNA vaccine; aging; immunosenescence; mRNA vaccine; nucleic acid vaccines.

Figure 1

Summary of age-related impairments in T cells, B cells, and antigen presenting cells responsible for vaccine-mediated responses. This schematic illustrates key changes in immune function with age, broken down into four primary regions: the thymus, circulation and skin, secondary lymphoid organs, and bone marrow. Thymic Involution (top panel) leads to decreased production of naïve CD4+ and CD8+ T cells and reduced T cell receptor (TCR) repertoire diversity. In circulation and skin (second panel), altered immune cell populations and function, including changes in antibody titers, macrophage pro-inflammatory cytokine release, and macrophage polarization are observed. Secondary lymphoid organs (third panel), including the spleen and lymph nodes, exhibit changes in T cell subsets, B cell function, and antigen-presentation. Bone marrow (bottom panel) experiences shifts in hematopoietic stem cell populations, reduced B cell and T cell progenitors, and altered macrophage signaling. Downward arrows indicate decreased function or numbers, while upward arrows indicate increased activity or numbers. Created in BioRender.

Figure 2

Comparative overview of mRNA and DNA vaccine design. Methods for (1) Routes of administration, (2) Delivery, and (3) Adjuvants for mRNA (right panel, red) and DNA (left panel, blue) vaccines are illustrated. APC, antigen-presenting cell; MHC, Major histocompatibility complex; PLGA, Poly(lactic-co-glycolic acid); PEI, Polyethylenimine; PBAE, poly(β-amino ester); CART, charge-altering releasable transporters; DLinDMA, 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane; DDA, dimethyl-dioctadecyl ammonium; ADA-1, Adenosine deaminase-1. Created in BioRender.