Clinical and immunological effects of mRNA vaccines in malignant diseases

Abstract

In vitro-transcribed messenger RNA-based therapeutics represent a relatively novel and highly efficient class of drugs. Several recently published studies emphasize the potential efficacy of mRNA vaccines in treating different types of malignant and infectious diseases where conventional vaccine strategies and platforms fail to elicit protective immune responses. mRNA vaccines have lately raised high interest as potent vaccines against SARS-CoV2. Direct application of mRNA or its electroporation into dendritic cells was shown to induce polyclonal CD4+ and CD8+ mediated antigen-specific T cell responses as well as the production of protective antibodies with the ability to eliminate transformed or infected cells. More importantly, the vaccine composition may include two or more mRNAs coding for different proteins or long peptides. This enables the induction of polyclonal immune responses against a broad variety of epitopes within the encoded antigens that are presented on various MHC complexes, thus avoiding the restriction to a certain HLA molecule or possible immune escape due to antigen-loss. The development and design of mRNA therapies was recently boosted by several critical innovations including the development of technologies for the production and delivery of high quality and stable mRNA. Several technical obstacles such as stability, delivery and immunogenicity were addressed in the past and gradually solved in the recent years.This review will summarize the most recent technological developments and application of mRNA vaccines in clinical trials and discusses the results, challenges and future directions with a special focus on the induced innate and adaptive immune responses.

Keywords: B cells; COVID19; Cancer; Immune response; T cells; Tumor-associated antigen; mRNA vaccine.

Fig. 1

Effects of mRNA vaccines on immunity. a Effects of exogeneous mRNA on innate immunity. Exogeneous mRNA can be sensed by TLRs in the endosomes as well as receptors like RIG-I and MDA5 in the cytosol. dsRNA can induce a strong IFN1 response. Peptides derived from the translated protein will be processed in the proteasome and presented on MHC-I and MHC-II molecules. b Effects of exogeneous mRNA on innate immunity. APCs can present exogeneous antigens on MHC-II to CD4+ T cells and cross-present on MHC-I to CD8+ T cells. CD4+ T cells provide help to B cells and CD8+ T cells. Finally, clonal expansion of antigen-specific B and T cells results in target cell elimination. c Risk of tumor immune-evasion. Tumors are capable of creating an immunosuppressive micro-environment by recruiting myeloid-derived suppressor cells (MDSCs), regulatory T cells, M2 macrophages and the production of immunosuppressive cytokines. Upregulation of exhaustion markers on T cells, or antigen loss on tumor cells can further drive immune-evasion, exemplarily. CPI might help to regain immunosurveillance. BioRender was used to create the figure

Fig. 2

Different locations of mRNA injection can modulate the induced immune response. The advantages and disadvantages of different delivery ways are listed. BioRender was used to create the figure