The dynamic of the virus-host interaction is subject to constant evolution, which makes it difficult to predict when the SARS-CoV-2 pandemic will become endemic. Vaccines in conjunction with efforts around masking and social distancing have reduced SARS-CoV-2 infection rates, however, there are still significant challenges to contend with before the pandemic shifts to endemic, such as the coronavirus acquiring mutations that allow the virus to dodge the immunity acquired by hosts. SARS-CoV-2 variants deploy convergent evolutionary mechanisms to sharpen their ability to impede the host’s innate immune response. The continued emergence of variants and sub-variants poses a significant hurdle to reaching endemicity. This underscores the importance of continued public health measures to control SARS-CoV-2 transmission and the need to develop better second-generation vaccines and effective treatments that would tackle current and future variants. We hypothesize that the hosts’ immunity to the virus is also evolving, which is likely to abet the process of reaching endemicity.

Self-replicating RNA viruses such as alphaviruses, flaviviruses, paramyxoviruses, and rhabdoviruses have been engineered as expression vectors for vaccine development. The prominent feature of self-replicating RNA viruses is their RNA-dependent RNA polymerase activity, which generates massive self-amplification of RNA in the cytoplasm of infected host cells leading to extreme levels of transgene expression. Infectious diseases have been targeted by overexpression of surface proteins of pathogens as antigens for vaccine development. Moreover, overexpression of tumor-associated antigens and immunostimulatory genes has been the basis for cancer vaccines. Proof-of-concept of robust antigen-specific immune responses and protection against challenges with lethal doses of infectious agents have been demonstrated. Likewise, vaccine development against various cancers has elicited strong immune responses and resulted in tumor regression and eradication, cure, and prolonged survival in animal tumor models. Good safety and immune responses have been achieved in clinical trials. The ERVEBO® vaccine, based on the vesicular stomatitis virus, has been approved for immunization against the Ebola virus disease.

The idea that proteins are the main determining factors in the functioning of cells and organisms, and their dysfunctions are the first cause of pathologies, has been predominant in biology and biomedicine until recently. This protein-centered view was too simplistic and failed to explain the physiological and pathological complexity of the cell. About 80% of the human genome is dynamically and pervasively transcribed, mostly as non-protein-coding RNAs (ncRNAs), which competitively interact with each other and with coding RNAs generating a complex RNA network regulating RNA processing, stability, and translation and, accordingly, fine-tuning the gene expression of the cells. Qualitative and quantitative dysregulations of RNA-RNA interaction networks are strongly involved in the onset and progression of many pathologies, including cancers and degenerative diseases. This review will summarize the RNA species involved in the competitive endogenous RNA network, their mechanisms of action, and involvement in pathological phenotypes. Moreover, it will give an overview of the most advanced experimental and computational methods to dissect and rebuild RNA networks.

m⁶A RNA methylation, a predominant type of RNA modification, is involved in regulating mRNA splicing, stability, and translation as well as the interaction between nucleoproteins and noncoding RNAs. Recent studies have revealed that m⁶A RNA methylation plays a critical role in the self-to-non-self-recognition of immune cells against endogenous mutations in cancer and exogenous organism-related infections. As an epigenetic mechanism, m⁶A RNA modification induces immune cell signal transduction, which is altered in the tumor microenvironment, as detected in liquid biopsy. Furthermore, m⁶A RNA methylation-related inflammation is involved in the cellular response to viral infections, including the emerging severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. Given the importance of the immune response in maintaining homeostasis in higher eukaryotes, m⁶A RNA methylation could be useful not only for the early detection of cancer but also for SARS-CoV-2 screening during a global pandemic.