Encyclopedia
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.
- mRNA vaccines
- COVID-19
- drug regulation
- gene therapy
1. Introduction
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.
2. COVID-19 mRNA
Conclusions
Although the principle of action of COVID-19 mRNA vaccines corresponds to the definition of gene therapy products (GTPs), they have been excluded from the regulation of GTPs by the regulatory agencies (US-FDA and EMA) and subjected to the regulation of vaccines against infectious diseases. No scientific or ethical justification is given for this exclusion, and there remain inconsistencies in the regulations. For example, under European and French regulations, a vaccine must contain an antigen, which is not the case for mRNA vaccines. These products could be considered “pro-vaccine”. In fact, mRNA vaccines do not contain an antigen, but make the vaccinee produce it. They can therefore be classed as pro-drugs or “pro-vaccine”. Special regulations should be drawn up for this type of product, insisting on potency controls, i.e., the quality, quantity, duration and sites of expression of the antigen of interest, as well as the toxicity of this antigen. As proposed at the start of 2020, the SARS-CoV-2 spike protein interacts with the renin- angiotensin system [1][2][3][101–103] and has a recognized toxicity that was known since before COVID-19 [4][104] and has been confirmed since [5][6][7][8][105–108].
According to European regulations, vaccines are human medicinal products and must therefore undergo the same controls, but not all of these controls are generally applied to vaccines against infectious diseases. With regard to the controls applied to mRNAs, it is worth noting that the degree of purity of the product is lower than that required for any drug: this is questionable for a new formulation and principle of action. It is also possible that batch heterogeneity was not detected by the batch release procedure. Impurities linked to this new formulation could pose safety problems; the presence and quantity of contaminating DNA from the template used to manufacture the RNA and of ds-RNA would need to be reassessed. The presence of antibiotic resistance genes in contaminating template DNA also raises safety issues.
Pharmacokinetic studies are not generally required for vaccines, except in the case of new formulations, which is the case here. However, extensive studies in this field would have been necessary, since they did not detect the wide distribution and persistence of mRNA, and its product, the spike protein, in the bodies of vaccinees, the passage of mRNA in breast milk, nor the possible passage through the placenta of vaccinated mothers. GTP regulations require these in-depth studies on the complete formulation (the lipid nanoparticle loaded with the mRNA corresponding to the drug product).
Because of this wide and persistent biodistribution, essential tests required for GTPs should have been carried out regarding: the risk of genotoxicity, genome integration and germ-line transmission, insertional mutagenesis, tumorigenicity, embryo/fetal and perinatal toxicity, long term expression, repeated toxicity and excretion in the environment (shedding in the seminal fluid, for example).
The long-term safety monitoring of GTPs is required over several years whereas, for vaccines, it is generally only carried out over a few weeks. This should not be acceptable, given the persistence of the drug product and the expressed protein. The known results of anti-cancer therapies and mRNA vaccines could lead us to anticipate problems of safety and efficacy. In the case of anti-cancer mRNAs, the vast majority of open-label clinical trials have been carried out on very small numbers of patients, with either unpublished or negative results [9][10][109,110]. Randomized studies also showed negative results, reporting more frequent adverse events in the treatment group [11][12][111,112]. Concerning infectious diseases, two trials of mRNA vaccines encapsulated in LNPs showed notable adverse effects. A trial of an mRNA vaccine against rabies showed numerous adverse effects superior to those of the classic vaccine, which is already very reactogenic, notably lymphopenia (this effect was also found for anti-COVID-19 mRNA vaccines) [13][113]. An influenza vaccine trial [14][114] showed severe adverse effects in humans (31 subjects were observed over only 43 days and at least 4 serious adverse effects were found). In a non-randomized trial against HIV [15][115], the response was inexplicably incomplete in some patients. According to another HIV trial of 15 participants against a placebo, immune responses were unsatisfactory and of limited duration [16][116]. The founder of BioNTech himself, Ugur Sahin, warned against the use of codon optimization, which can alter translation speed and lead to misfolding. He also underlined the potential toxicity of unnatural nucleotides. He also mentioned the wide biodistribution of mRNA injected intramuscularly. He reminded us that we should fear the appearance of anti-self mRNA antibodies in patients suffering from autoimmune diseases [17].the use of codon optimization, which can alter translation speed and lead to misfolding. He also underlined the potential toxicity of unnatural nucleotides. He also mentioned the wide biodistribution of mRNA injected intramuscularly. He reminded us that we should fear the appearance of anti-self mRNA antibodies in patients suffering from autoimmune diseases [27].
The role of regulatory agencies is to ensure the safety and efficacy of medicines. The COVID-19 pandemic emergency has accelerated the timetable for the production and clinical use of COVID-19 vaccines; it is, therefore, possible that certain safety aspects have not been fully addressed. It is, therefore, important to take these aspects into account in the future, so as not to undermine public confidence in vaccines in general.
The WHO declared an end to the emergency phase of the COVID-19 pandemic at the beginning of May 2023 but will continue to authorize the use of the Emergency Use Listed (EUL) procedure. The emergency authorization of vaccines should be transformed into prequalification via a smooth transition [18][117]. However, a wide-ranging public discussion should be opened on this transition to the routine use of mRNA vaccines, without them being subject to the controls required for GTPs.
In the EMA document designed to regulate the clinical evaluation of new vaccines from 2023, there is no mention of mRNA vaccines, and it is still specified that vaccines contain antigens; this document would therefore not apply to mRNA vaccines that do not contain antigens. It is once again specified that nonclinical pharmacokinetic studies might be applicable when new delivery systems are employed or when the vaccine contains novel adjuvants or excipients. It is a pity that these points have not been specified specifically for mRNA vaccines [19][118]. An article from early 2021 [20][119] emphasized the need for further studies to ensure the quality, efficacy and safety of mRNA vaccines; it was written before these products were marketed. It seems important to clarify which additional controls should be required in light of the detailed results of the preclinical trials and safety data published in the post-marketing phase.
In the future, it should be discussed whether all mRNA-based products should be subject to the same regulations and controls, whether or not they are considered vaccines. It is not justifiable to subject therapeutic mRNAs to strict controls when they are intended for patients representing a small proportion of the human population, and to exclude from these controls mRNA vaccines intended for the majority of the healthy human population.
