In France, the vaccination campaign against the covid-19 epidemic is due to start in late December 2020. In the first instance, a single vaccine will be used: the covid-19 mRNA vaccine BNT162b2 (Comirnaty°), from the pharmaceutical companies Pfizer and BioNTech, which has been assigned the international nonproprietary name (INN) tozinameran. The first population to whom the French authorities have chosen to offer the vaccine are residents of nursing homes and similar facilities, and health professionals who work in these facilities and are at increased risk of developing severe covid-19, mainly because of a health problem (1).

What are the main data available as of late 2020 from the clinical evaluation of this vaccine in the population targeted by this first phase of France’s covid-19 vaccination campaign?

A messenger RNA vaccine with lipid and PEG nanoparticles but no adjuvants or preservatives. The tozinameran vaccine is a messenger ribonucleic acid (mRNA) vaccine. mRNA is a molecule that transports genetic information. Each strand of mRNA contains a code that enables cells to synthesise a specific protein in their cytoplasm. The principle behind mRNA vaccines is that the mRNA administered encodes the protein against which an immune response is to be mounted. The mRNA must enter host cells (but without entering the nucleus, where the host DNA resides), these cells must then produce the viral protein encoded by the mRNA and, finally, this viral protein should elicit an immune response. The mRNA strands in the vaccine are contained within lipid nanoparticles, to protect them from destruction in the extracellular environment and to facilitate their entry into host cells (2). The lipid nanoparticles in the tozinameran vaccine also contain polyethylene glycol (PEG) 2000 (3). This vaccine contains no adjuvants or preservatives.

In the short term, marked reduction in the number of cases of symptomatic, laboratory-confirmed covid-19 in one clinical trial. The clinical evaluation data available on the tozinameran vaccine as of December 2020 centre on a randomised trial in which the participants, aged 16 years or older, received two injections, 21 days apart, of either the vaccine or placebo. 42% of recipients were over 55 years of age, 21% were aged 65 or older, and 4% were aged 75 or older (3,4). Among the roughly 40 000 trial participants, 3% had already had confirmed covid-19 and 46% had at least one risk factor for developing severe covid-19 other than their age. The commonest risk factor, present in 35% of trial participants, was obesity. Any chronic conditions they had were considered stable (3).

Neither the trial participants nor the investigators who evaluated efficacy and adverse effects knew which product the participants had received. But 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.

Efficacy was evaluated by recording the number of cases of symptomatic, laboratory-confirmed covid-19 that occurred from day 7 onwards after the second injection (the primary endpoint). After this second injection, at a time when 80% of the participants had been followed up for at least 1 month and 44% for at least 2 months, 9 cases of covid-19 had occurred in the vaccine group, versus 169 in the placebo group, i.e. the vaccine reduced the risk of developing covid-19 by 94.6% (95% “credible interval”: 89.9% to 97.3%). When all the cases of laboratory-confirmed covid-19 that occurred during the trial are considered, including those that occurred after the first injection, the vaccine appeared to have a preventive effect from about day 15 after the first injection (3).

Very few cases of covid-19 occurred among the 1093 patients who had been infected with Sars-CoV-2 before the trial (positive serology), with no difference between the vaccine and placebo groups (3).

Over the entire follow-up period, one person in the vaccine group developed a severe form of laboratory-confirmed covid-19, versus 9 cases in the placebo group. The relative risk reduction of vaccination for severe disease was therefore 89%, but the 95% confidence interval (95CI) was 20% to 100% (3). This very wide confidence interval shows that the accuracy of this result is highly uncertain, due in large part to the small number of cases reported.

Uncertainty increases with age. Vaccines are generally less immunogenic in older adults than in young adults, which may make vaccination less effective in elderly patients (5).

The vaccine did not appear any less effective in preventing covid-19 (all severities combined) from day 7 after the second injection in vaccinees aged 55 years or older than in the younger vaccinees. Its calculated efficacy in vaccinees aged between 65 and 74 years was about 93%, but with a greater margin of uncertainty (95CI: 53% to 100%) (3).

None of the 805 vaccinees aged 75 or older developed covid19, versus 5 of the 812 participants of this age who received placebo. The 95% confidence interval of the relative risk reduction is very wide: 12.1% to 100% (3). This result shows that the trial was not designed to evaluate the efficacy of the vaccine in adults aged 75 years or older.

Among the trial participants with at least one risk factor for severe covid-19, such as hypertension, diabetes or obesity (most of whom were under 65 years of age), the efficacy of the vaccine was similar to that reported for the whole study population: relative risk reduction for covid-19 of 95% (95CI: 88% to 99%) (3).

Likely adverse effects. As of late 2020, data on the medium- and long-term effects of mRNA vaccines are lacking, because no other such vaccines have yet been marketed for human use anywhere in the world. Unlike DNA, mRNA is not incorporated into the cell’s genetic material. The tozinameran vaccine is likely to provoke hypersensitivity reactions and anaphylactic reactions due to the presence of polyethylene glycol (PEG) (2,6,7).

The other foreseeable adverse effects of this vaccine are those shared by vaccines in general: local reactions at the site of injection and systemic reactions (fever, chills, fatigue, headache and muscle pain) (5). Vaccines can also sometimes provoke rare autoimmune diseases such as Guillain-Barré syndrome; no cases were reported with the tozinameran vaccine during evaluation (8). A phenomenon reported in animal studies was vaccine-associated worsening of an infection with Sars-CoV-1, another coronavirus. On the basis of these data, the possibility of the vaccine worsening Sars-CoV-2 infection is a hypothesis that must be taken into account and evaluated (2).

Local and systemic adverse effects very common. The main adverse events reported in the trial of the tozinameran vaccine, in about 40 000 persons, were: injection site reactions (pain, redness, swelling) in about 75% of vaccine recipients after each injection, versus 12% in the placebo group; and systemic reactions (such as fever, sometimes above 39°C, fatigue, headache, chills and muscle pain) in about 65% of vaccine recipients after each injection, versus about 40% in the placebo group. The median duration of systemic reactions was 1 day. Some systemic reactions were so intense that they severely restricted daily activities. Medication to alleviate fever or pain was taken by about 20% of vaccinees after the first injection and about 40% after the second injection, versus about 10% of participants receiving injections of placebo (3,4).

The other adverse events reported more frequently in the vaccine group than in the placebo group were lymphadenopathy (64 cases versus 6 with placebo) and facial paralysis (4 cases versus none) (3).

Older adults did not experience more adverse effects than younger participants (3). The use of the tozinameran vaccine in immunisation campaigns has already begun in some countries, including the United Kingdom, and a few cases of anaphylactic reactions have been reported (9).

In practice, many uncertainties, as with any new drug. While awaiting a thorough analysis of the data, the following points from the main clinical trial of the tozinameran covid-19 vaccine will help inform the first patients to be offered the vaccine:

• The main trial included about 40 000 participants aged 16 years and over. About 20% of them were older than 65 years of age, and 46% had one or more risk factors for developing severe covid-19 other than age.
   
• This trial shows that this vaccine is highly effective at preventing covid-19 in the short term, although the duration of this effect is unknown.
   
• Although this trial was not designed to evaluate efficacy in vaccinees aged 75 years or older (fewer than 2000 participants), taking all the trial data into account, it is likely to have some (albeit unknown) degree of efficacy.
   
• The main known adverse effects of this vaccine are local and systemic reactions, which are very common and sometimes severe, and anaphylactic reactions, which are rare. No significant safety signals emerged, but many unknowns remain, 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, especially in patients over the age of 75.

These points should be explained, taking whatever time is necessary, including to those who may have trouble taking in and understanding this information. It is important to give the persons concerned sufficient time to think it over before making a decision one way or the other.

©Prescrire 23 December 2020

Sources:

• "Vaccin covid-19 à ARN messager tozinaméran (Comirnaty° des firmes Pfizer et BioNTech) et personnes âgées : quelques données, beaucoup d'incertitudes" Application Prescrire 23 December 2020.

1. HAS "Stratégie de vaccination contre le Sars-Cov-2. Recommandations préliminaires sur la stratégie de priorisation des populations à vacciner" 27 November 2020: 58 pages.
2. HAS "Aspects immunologiques et virologiques de l'infection par le Sars-Cov-2. Variabilité génétique, réponses immunitaires, plateformes vaccinales et modèles animaux" 25 November 2020: 134 pages.
3. US FDA "Vaccines and related biological products advisory committee meeting. Briefing document: Pfizer-BioNTech COVID-19 vaccine" 10 December 2020: 53 pages.
4. Polack FP et al. "Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine" N Engl J Med 2020: 13 pages (+ Appendices: 12 pages; + Protocol: 376 pages). www.nejm.org accessed 11 December 2020.
5. Prescrire Rédaction "Vaccin grippal quadrivalent à 60 microg par souche (Efluelda°) chez les personnes âgées d'au moins 65 ans. Pas de progrès décisif par rapport au vaccin grippal "classique" à 15 microg par souche" Rev Prescrire 2021 (digital version, in French).
6. Garvey LH, Nasser S "Allergic reactions to the first COVID-19 vaccine: is polyethylene glycol (PEG) the culprit?" Br J Anaesth 2020. https://doi.org/10.1016/j.bja.2020.12.020
7. Verhoef JJF and Anchordoquy TJ "Questioning the use of PEGylation for drug delivery" Drug Deliv Transl Res 2013; 3 (6): 499-503.
8. Prescrire Rédaction "Maladie auto-immune d'origine médicamenteuse" Rev Prescrire 2017; 37 (403): 346-353.
9. Medicines and Healthcare products Regulatory Agency "Confirmation of guidance to vaccination centres on managing allergic reactions following COVID-19 vaccination with the Pfizer/BioNTech vaccine" 9 December 2020: 3 pages. www.gov.uk accessed 11 December 2020.
    

For more information:

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