A messenger RNA vaccine, similar to tozinameran. The vaccine mRNA-1273 Sars-CoV-2 is a messenger ribonucleic acid (mRNA) vaccine. It is very similar to tozinameran (> HERE). The strands of mRNA in both of these vaccines encode a protein on the surface of the virus, called the spike protein. The strands of mRNA are contained within lipid nanoparticles that differ between the two vaccines, although both contain polyethylene glycol (PEG) 2000. Neither vaccine contains adjuvants or preservatives (1,2).

A clinical trial in about 30 000 adults, including about 7600 health professionals. The clinical evaluation data on the vaccine mRNA-1273 Sars-CoV-2 available in early January 2021 centre on a randomised placebo-controlled trial in about 30 000 participants aged 18 years or older, who received two injections, 28 days apart, of either the vaccine or placebo. Half of the participants were aged 53 years or older. About 25% were aged 65 or older, and about 5% were 75 or older. The absence of prior covid-19 was confirmed in 95% of all the participants. 22% had at least one risk factor for developing severe covid-19 other than their age. About 25 000 participants had an occupation that exposed them to a high risk of contracting covid-19, including about 7600 health professionals (1).

In this trial, vaccine or placebo was administered over the summer and autumn of 2020 in the US, before the identification of certain variants of the Sars-CoV-2 virus, isolated in December 2020 mainly in the UK and South Africa (1,3).

Neither the trial participants nor the investigators who evaluated efficacy and adverse effects knew which product the participant had received. But as in the main trial to evaluate the efficacy of tozinameran, personnel responsible for receiving, preparing or injecting the products knew whether they were handling the vaccine or placebo. The possibility of the disclosure of this information to participants or investigators therefore existed (4). It is also plausible that some participants guessed which product they received, because the vaccine’s local or systemic adverse effects are very common (see below). The uncertainty over whether blinding had been effectively maintained reduces the quality of the evidence provided by this trial.

In the short term, marked reduction in the number of cases of symptomatic covid-19 in the vaccine group. Efficacy was evaluated by recording the number of cases of symptomatic, laboratory-confirmed covid-19 that occurred from day 14 onwards after the second injection (the primary endpoint). After a median follow-up of 9 weeks after the second injection, 12 cases of covid-19 had occurred in the vaccine group, versus 187 in the placebo group, i.e. the vaccine reduced the risk of developing symptomatic covid-19 by 94% (95% confidence interval (95CI): 89% to 97%). The vaccine appeared to have a preventive effect from about day 15 after the first injection (1,5).

Only one of the 675 patients with prior, documented Sars-CoV-2 infection before the trial developed covid-19, and this person was in the placebo group (1,5).

From day 14 after the second injection, one person in the vaccine group developed severe covid-19 (although this case was not taken into account by the trial investigators because it was confirmed by RT-PCR in a pathology laboratory external to the trial) versus 30 cases in the placebo group. Nine of these 30 patients were hospitalised and one died from covid-19 (1).

Effective in adults under the age of 65 years with risk factors for developing severe covid-19; degree of efficacy unknown after 75 years of age. In participants under the age of 65 years with at least one risk factor for developing severe covid-19, such as chronic respiratory disease, cardiac disease, severe obesity or diabetes, the relative reduction in the risk of covid-19, all severities combined, from day 14 after the second injection was 94% (95CI: 77% to 99%) (5). Its efficacy in adults aged 65 years or older was 86%, with an even wider 95CI of 61% to 95% (1). The wider confidence intervals obtained when analysing these subgroups than when analysing all the participants combined reflect greater uncertainty over the relative risk reduction in these subgroups.

This trial was not designed to evaluate the efficacy of the vaccine mRNA-1273 Sars-CoV-2 in adults aged 75 years or older, who accounted for only about 5% of the trial participants. The only data available in this age group come from an interim analysis in which only 3 participants, all in the placebo group, developed covid-19. These data are insufficient for assessing the degree to which this vaccine reduces the risk of developing covid-19 in patients over the age of 75, although it is likely to have some efficacy in light of all the results obtained (1,5).

Local and systemic adverse effects, including hypersensitivity reactions. The main foreseeable adverse effects of mRNA vaccines are those shared by vaccines in general: local reactions at the injection site and systemic reactions. The possibility of the vaccine worsening Sars-CoV-2 infection is a hypothesis that must be taken into account, in view of the findings of certain animal studies with a Sars-CoV-1 coronavirus vaccine. Hypersensitivity reactions and anaphylactic reactions are likely due to the presence of polyethylene glycol (PEG). Many unknowns remain over the adverse effects of mRNA vaccines as of early 2021, due to the lack of medium- and long-term data.

In the placebo-controlled trial with about 30 000 participants, an analysis by the US Food and Drug Administration (FDA) reported that 92% of vaccine recipients had local reactions in the 7 days following an injection, versus 29% in the placebo group, mainly consisting of pain and axillary lymphadenopathy. The incidence of severe local reactions was 9% in the vaccine group, versus 1% in the placebo group. The median duration of local reactions was 2 to 3 days (1).

Systemic adverse events in the 7 days following vaccination were reported in 83% of vaccine recipients versus 53% with placebo, mainly consisting of fatigue, headache, muscle or joint pain, chills, fever, nausea or vomiting. The median duration was 2 days. A minority of patients had systemic reactions lasting for at least 7 days. The incidence of severe reactions after the second dose was 16% in the vaccine group versus 4% in the placebo group (1).

Hypersensitivity reactions were reported in 1.5% of participants in the vaccine group versus 1.1% in the placebo group. No serious reactions or anaphylactic reactions occurred during the trial (1). A serious allergic reaction was however reported outside the clinical trial in a person with a seafood allergy (6). One case of lip angioedema and two cases of facial swelling were reported during the trial, all three in women in the vaccine group who had previously received dermal filler injections. Similar disorders have already been reported during viral infections. Three cases of facial paralysis occurred in the vaccine group (which resolved in two cases) versus one case in the placebo group (1).

Practical differences between the two mRNA vaccines: prevent errors. The vaccine mRNA-1273 Sars-CoV-2 by Moderna must be stored frozen between -25°C and 15°C (typical freezer temperatures). Once thawed, the vaccine has a shelf life of 30 days when kept refrigerated between 2°C and 8°C, and 12 hours between 8°C and 25°C. Each dose of mRNA-1273 Sars-CoV-2 vaccine consists of 0.5 ml of dispersion, taken directly from the vial. Each vial contains 10 doses, all of which must be used within 6 hours after withdrawal of the first dose (7,8).

All of these characteristics are different from those of the vaccine tozinameran, marketed by Pfizer and BioNTech. Tozinameran must be stored between -80°C and -60°C. Once thawed, it has a shelf life of 5 days when refrigerated between 2°C and 8°C, or 2 hours at room temperature (not exceeding 30°C). In addition, tozinameran must be diluted before use, by adding 1.8 ml of 0.9% sodium chloride solution to each vial. Each dose of tozinameran consists of 0.3 ml of dispersion, taken directly from the vial. Each vial contains 5 doses, to be used within 6 hours after dilution (7,8).

Teams dealing with both vaccines at the same time will need to implement measures to prevent errors, such as marking the packaging with the time and date of thawing, and the time and date by which the doses must be used.

The fact that the mRNA-1273 Sars-CoV-2 and tozinameran vaccines are supplied in multidose vials is likely to lead to errors in which patients receive several doses instead of one. Such errors have already been reported (9).

In practice, short-term efficacy in adults, but uncertainties remain. While awaiting a thorough analysis of the data, the following points from the main comparative clinical trial of two injections of the mRNA-1273 Sars-CoV-2 vaccine, 28 days apart, will help inform patients who are offered this vaccine:

• This trial included about 30 000 participants aged 18 years and over. About half of them were over 53 years of age. About 25% were older than 65 years, and about 22% had one or more risk factors for developing severe covid-19 other than their age.
• This trial shows that overall, this vaccine is highly effective at preventing symptomatic covid-19, including severe forms, in the short term; but as with tozinameran, the duration of this effect is unknown.
• This vaccine appears to be highly effective in the short term at preventing covid-19 in adults under the age of 65 years with risk factors for developing severe covid-19 other than age, as well as in adults aged 65 years to 75 years, but with a slightly greater margin of uncertainty.
• This trial was not designed to evaluate the efficacy of the mRNA-1273 Sars-CoV-2 vaccine in adults aged 75 years or older, who accounted for only about 5% of trial participants. As with tozinameran, taking all the trial data into account, it is likely to have some (albeit unknown) degree of efficacy in this age group.
• The main known adverse effects of the vaccine are local and systemic reactions, which are very common and sometimes severe, and hypersensitivity reactions. No significant safety signals emerged, but many unknowns remain concerning its adverse effects, due to the fact that only short-term follow-up data are available, as is the case for any new drug, vaccine or other treatment.

In short, as of early 2021, the knowns and unknowns concerning the vaccines mRNA-1273 Sars-CoV-2 and tozinameran (> HERE) are very similar. This information, as well as information about the risk of contracting a severe form of covid-19, should be given to everyone offered this vaccine, taking whatever time is necessary, including to those who may have trouble taking in and understanding it. It is essential to give sufficient time to patients who wish to think it over before making a decision one way or the other.

©Prescrire 6 January 2021

Sources:

• "Vaccin covid-19 à ARN messager de la firme Moderna : quelques données et des incertitudes, comme avec le vaccin tozinaméran (Comirnaty°, des firmes Pfizer et BioNTech)" Application Prescrire 6 January 2021.

1. FDA "FDA briefing document. Moderna COVID-19 vaccine" 17 December 2020: 54 pages.
2. Prescrire Editorial Staff "The covid-19 messenger RNA vaccine tozinameran (Comirnaty°, from Pfizer and BioNTech) in elderly patients: limited data, many uncertainties" 23 December 2020.
3. "A study to evaluate efficacy, safety, and immunogenicity of mRNA-1273 vaccine in adults aged 18 years and older to prevent covid-19. NCT04470427". www.clinical.trials.gov accessed 30 December 2020.
4. Moderna TX "A phase 3, randomized, stratified, observer-blind, placebo-controlled study to evaluate the efficacy, safety, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine in adults aged 18 years and older. Clinical study protocol" 23 December 2020: 158 pages.
5. Moderna TX "MRNA-1273. Sponsor Briefing document" 17 December 2020: 84 pages.
6. APMNews "Un décès après vaccination contre le covid-19 en Suisse, pas de lien démontré" 30 December 2020: 2 pages.
7. European Commission "SPC-Comirnaty" 29 December 2020: 15 pages.
8. Health Canada "Monograph-Moderna COVID-19 Vaccine" 23 December 2020: 25 pages.
9. AFP "covid-19: huit personnes reçoivent par erreur cinq doses de vaccin en Allemagne" 28 December 2020: 1 page.
    

For more information:

• "Covid-19: Follow Prescrire's independent, evidence-based analysis of the pandemic" > HERE