Since the reporting of the first cases of coronavirus in China and the publication of the first sequence of SARS-CoV-2 in December 2019, the virus has undergone numerous mutations. In Europe, the spring outbreak (March–April) was followed by a drop in the number of cases and deaths. The disease may have evolved into a milder form. The increase in PCR-positive cases in late summer 2020 did not lead to the expected increase in hospitalizations, ICU admissions, and deaths, based on the severity of the disease in the spring. This difference in disease severity could be due to factors independent of the virus or to the evolution of the virus. This review attempts to identify the mutations that have appeared since the beginning of the pandemic and their role in the temporal evolution of the pandemic. There are a cell and humoral type cross-reactivity in a large part of the population to common cold coronaviruses (HCoVs) and SARS-CoV-2. Evolutionarily important mutations and deletions have emerged in the SARS-CoV-2 genes encoding proteins that interact with the host immune system. In addition, one of the major mutations (in viral polymerase) is logically associated with a higher frequency of mutations throughout the genome. This frequency fluctuates over time and shows a peak at the time when the epidemic was most active. The rate of mutations in proteins involved in the relationship to the immune system continues to increase after the first outbreak. The cross-reactivity on the 1 hand and the viral mutations observed on the other hand could explain the evolution of the pandemic until the summer of 2020, partly due to the evolution of the virus in relation to the host immune system. The immunization campaign began in December 2020: concerns are emerging about a possible escape of the circulating variants vaccines in early 2021. These variants could also escape immunity acquired through infection with the 2020 strains.

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic.