IJMS | Free Full-Text | mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues

IJMS | Free Full-Text | mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues Abstract 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. 1. Introduction The regulation of medicines and vaccines is a little-known but very important subject. Indeed, health products must undergo very strict controls, as a principle, in order to control their efficacy and safety profile. The anti-COVID-19 mRNA vaccines are the first mRNA vaccines marketed. mRNA vaccines, which represent a new class of vaccine, should be subject to more controls than conventional vaccines because they are based on several new technologies [1]. Although incompletely defined, the mode of action of mRNA vaccines [2] should classify them as gene therapy products (GTP) [3]. But mRNAs as vaccines against an infectious disease have been excluded from GTP regulation by US and EU regulations [4]. No specific regulations existed before the year 2020 for mRNA vaccines. “The current guidelines either do not apply, do not mention RNA therapeutics, or do not have widely accepted definition” [5]. Regulatory agencies therefore had to adopt an emergency procedure to monitor the testing of these products, the rolling review. In rolling reviews, data are submitted and reviewed as they become available before the full data package is available and specific controls for this new platform have been requested [6]. The aim of this study is to compare the controls required by GTP regulations with those actually applied to mRNA COVID-19 vaccines. Some of the controls required for GTPs were not required for mRNA COVID-19 vaccines, probably because of the pandemic emergency that required the rapid development of SARS-CoV-2 vaccines. Potential safety issues arising from the absence of these controls will be discussed. This is all the more urgent as manufacturers are planning to replace certain “classic” vaccines with mRNA vaccines [2], starting with influenza vaccines. Indeed, Sanofi is launching a clinical trial of the first mRNA-based seasonal flu vaccine candidate [7] and Moderna has many mRNA vaccines in clinical trials (COVID-19, influenza, human metapneumovirus, parainfluenzas, RSV, HCoV, CMV, EBV, HSV, varicella, herpes, HIV, Zika, Nipah), in particular a phase 3 trial of the flu vaccine [8]. A phase 1 clinical trial is being launched for an mRNA-LNP influenza vaccine [9]. For these flu vaccines, emergency approval should not apply and the requirement for these additional studies should not be exceeded. In addition, cancer “vaccines” are being announced (e.g., Moderna and Merck are partnering in trials of mRNA-4157/V940, an anti-melanoma “vaccine” combined with Keytruda—a monoclonal antibody directed against the programmed cell death receptor, PD-1) that acts by enhancing the ability of the body’s immune system to detect and fight tumor cells, by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating the anti-T cell response, particularly the antitumor response [10]). We must be very vigilant about the term vaccine associated with therapeutic drugs, particularly with regard to the regulations that apply to them. These therapeutics are not vaccines against infectious diseases and must therefore continue to comply with GTP regulations.