Third-Generation Vaccines: Features of Nucleic Acid Vaccines and Strategies to Improve Their Efficiency

Abstract

Gene immunization comprises mRNA and DNA vaccines, which stand out due to their simple design, maintenance, and high efficacy. Several studies indicate promising results in preclinical and clinical trials regarding immunization against ebola, human immunodeficiency virus (HIV), influenza, and human papillomavirus (HPV). The efficiency of nucleic acid vaccines has been highlighted in the fight against COVID-19 with unprecedented approval of their use in humans. However, their low intrinsic immunogenicity points to the need to use strategies capable of overcoming this characteristic and increasing the efficiency of vaccine campaigns. These strategies include the improvement of the epitopes' presentation to the system via MHC, the evaluation of immunodominant epitopes with high coverage against emerging viral subtypes, the use of adjuvants that enhance immunogenicity, and the increase in the efficiency of vaccine transfection. In this review, we provide updates regarding some characteristics, construction, and improvement of such vaccines, especially about the production of synthetic multi-epitope genes, widely employed in the current gene-based vaccines.

Keywords: adjuvants; nucleic acids; synthetic genes; vaccines.

Figure 1

Activation of immunological pathways generated by nucleic acid vaccines. After the vaccine administration, the nucleic acids can be introduced into the dendritic cell through delivery mechanisms such as electroporation and lipidic nanoparticles. (1) Represented by the electric ray, the DNA electroporation facilitates the vaccine entry into the cell through transmembrane destabilization and favors the access of the genetic material to the nucleus and its subsequent transcription. (2) After that, the mRNA is formed and undergoes post-transcriptional modifications, allowing it to escape the nucleus and reach the cytoplasm. (3) The routes for DNA and mRNA vaccines are the same, with the translation of antigen occurring after the endocytosis of the mRNA vaccine. (4) The antigenic proteins processed by proteasomes generate epitopes that are associated with antigen processing (TAP), transported to endoplasmic reticulum, and carried in MHC-I molecules through the Golgi vesicles to be displayed on the cell surface. (5) Thus, MHC-I presenting antigen epitopes and costimulation signals activate naive CD8+ T lymphocytes leading to the production of effector cytotoxic cells, and the induction of immunological memory. (6) Furthermore, exogenous proteins released by transfected cells such as keratinocytes and myocytes can be recognized directly by B cells or phagocytosed by DCs, processed, and presented by MHC-II. (7) In this case, they can activate antigen-specific CD4+ T lymphocytes that expand into differentiated subtypes, release cytokines, and interact with B lymphocytes, leading to a strong humoral response. After antigen stimulus, some lymphocytes migrate to the different lymph nodes as memory cells (or sentinel cells) and are ready for an eventual infection.

Figure 2

Functions of adjuvants and linkers in the synthetic antigen. They are sequences that help to cleave the peptide formed and stimulate the immune response, respectively.