No 51/52b - 2020
On 21 December 2020, the first COVID-19 vaccine was authorised by the European Medicines Agency (EMA) and the EU Commission. The vaccine, which was coined Comirnaty®, is manufactured by Pfizer/BioNTech, who have already achieved emergency use authorisations in some countries, including Great Britain and the US, where a vaccination scheme has been initiated.
In the coming days, Denmark receives approx. 47,000 doses in two batches. The first batch consists of ten trays each counting 195 vials, corresponding to 9,750 doses. Once the vaccines are received at Statens Serum Institut (SSI) on 26 December, they will be prepared and released for distribution. Thus, the vaccination scheme will likely be initiated on 27 December. No later than by 2 January 2021, the SSI expects to receive the second batch with an additional 37,000 doses. In weeks 1-7, each week is expected to see the delivery of an additional 47,000 doses. From week 8 to week 13, the weekly number of vaccines received is expected to increase slightly.
In the EU, the vaccine has achieved a so-called conditional marketing authorisation. This means that the manufacturer of the vaccine must continue to provide data to the EMA after having received the conditional authorisation. A conditional authorisation is valid for one year and may be extended annually. Once the authorities have received all of the agreed documentation, the conditional authorisation may be changed to a normal authorisation.
The vaccine is the first in a series of newly developed vaccines that are expected to be approved for use against COVID-19 in the coming period. Limited amounts of Comirnaty® will initially be provided in the course of a prolonged period of time. Therefore, these vaccine doses will need to be prioritised following guidelines established by the Danish Health Authority’s Notification on prioritisation of target groups and distribution of vaccine against COVID-19 (in Danish language).
The vaccination schedule, including its various phases and the handling of vaccination against COVID-19, is described in detail (in Danish language) in the following publications by the Danish Health Authority: Organisation of the COVID-19 vaccination efforts and Guidelines on the handling of COVID-19 vaccination.
Information about the basis for the authorisation, product information, patient information leaflets and frequently asked questions and answers relating to Comirnaty® are available at the website of the Danish Medicines Agency (in Danish language).
In connection with the initiation of the vaccination scheme, various monitoring systems have been established:
- The Danish Medicines Agency monitors the safety of the vaccines. All newly registered vaccines will be subject to an enhanced duty of notification during the first two years. The Danish Medicines Agency closely monitors all COVID-19 vaccines after they have been approved to ensure that measures may be taken if the vaccine appears to be associated with an increased risk. This may include side effects that have not been detected in the trials or it may be known side effects that occur more frequently than was the case in the trials. Monitoring is, among others, done through citizens’ and healthcare workers’ notification of adverse events. Additionally, research-based projects have been initiated to further assess the adverse event profile of the vaccine.
- Statens Serum Institut monitors the coverage of the vaccination scheme and its overall effect in the population. Coverage will be published at the SSI web site, initially by age group and region of residence, subsequently also by risk group. The effect of the vaccine among those who have been vaccinated may be measured no sooner than approx. two months after the vaccination scheme has been initiated, but regular monitoring will be conducted as from then on.
About Pfizer/BioNTech Comirnaty®
The vaccine is a so-called mRNA vaccine, and this is the first time ever that a vaccine of this type has been developed and approved. mRNA is a non-infectious vaccine technology that contains neither active nor inactive virus. Therefore, vaccination carries no risk of infection. The “vaccine antigen” in the vial consists of slightly modified messenger RNA incapsulated in a protective layer of nanolipid that codes for the spike protein located on the surface of new corona virus (SARS-CoV-2) and which, in the body, is the antigen recognised by the human immune system.
Following injection into a muscle, the mRNA will be absorbed in muscle cells from where it is transported to the cell’s protein synthesis centre (ribosomes). Here, the mRNA code is read via so-called translation, and the spike protein is produced. The spike protein is subsequently transported out of and fixed on the surface of the muscle cells and to a certain extent to the bloodstream.
Subsequently, the spike protein is presented to the B and C cell immune system. This means that the body forms neutralising antibodies via B lymphocytes and that a specific T-cell-mediated immune response is formed. The mRNA is decomposed in the body via the normal cellular decomposition systems shortly after the cell has finished using the mRNA code.
The vaccine is formulated as a multi-dose vaccine in which every vial holds antigen corresponding to a minimum of five doses (each with 30 micrograms of mRNA embedded in lipid nanoparticles), which need to be diluted using unpreserved isotonic saline prior to injection; see details below.
The vaccination scheme of this vaccine consists of two 0.3 mL doses normally given at a minimum 21-day interval. (The shortest interval studied in the phase-3 study was 19 days). At intervals shorter than 19 days, the second vaccination is repeated. This extra vaccination is given 21 days after the early-administered second dose. In principle, no maximum interval exists, but in the current epidemic situation, if it cannot be given on the 21nd day, the second dose should be given as soon as possible thereafter.
The effect of the vaccine
The vaccine was tested in a phase 3 clinical trial including approx. 43,500 participants aged 16 years or above who were randomly allocated to receive either the test vaccine or placebo (saline). The primary endpoint was protection against laboratory-verified infection with SARS-CoV-2, i.e. COVID-19, in COVID-19-naive persons, whereas one of the secondary endpoints included persons who could previously have had COVID-19.
For the primary endpoint, eight infections were found in fully vaccinated persons in the control group (a minimum of seven days after the second vaccination) followed for 2,214 person years; in the placebo group, the corresponding figure was 162 infections observed during 2,222 person years. This yields a calculated 95.0% vaccine efficacy (point estimate) under controlled conditions (95% CI: 90.3% to 97.6%).
Among participants aged 65 years and above and 75 years and above without signs of previous COVID-19 infection, the protective effect was at the same high level; 94.7% (95% CI: 66.7% to 99.9%) and 100.0% (95% CI:-13.1% to 100.0%), respectively, but, as shown, with a broader confidence interval and a statistically non-significant vaccination effect. (In the group aged 65 years and above, the vaccine group and control group counted one case among 3,848 vaccinated persons and 19 cases among 3,880 placebo-vaccinated persons, respectively. In the group aged 75 years and above, these figures were zero among 774 vaccinated persons and five among 785 placebo-vaccinated persons).
A separate analysis showed no significant difference in protective effect for persons without an increased risk compared with persons who had one or more comorbidities causing them to be at increased risk of severe COVID-19 infection, e.g., asthma, BMI > 30, chronic obstructive pulmonary disease (COPD), diabetes or hypertension.
The median follow-up period was two months, the short duration of which was, of course, due to the accelerated development period for the first assessment of the phase-three trial by 9 October 2020.
After the first vaccine doses, a vaccine effectiveness of 52% was found (95% CI: 29.5% to 68.4%). (But vaccinees will not enjoy optimal protection until seven days after the second vaccination). It currently remains unknown for how long the protection will persist. This applies to the first and second dose alike. This will be explored in follow-up studies conducted in Denmark and abroad, cf. above.
It also remains unknown if the vaccine protects against asymptomatic infection or a “carrier state” with SARS-CoV-2. This will also be investigated in follow-up studies.
Who may be vaccinated
Persons aged 16 years or more with a view to active protection against SARS-CoV-2. For contraindications and precautions, please see below.
In the clinical trial on Comirnaty®, safety was assessed two months after the administration of the second dose among 19,067 persons (9,531 in the vaccine arm and 9,536 in the placebo arm). Very common (> 1/10) side effects were headache, joint and muscle pain/soreness, injection site pain and swelling, fatigue, chills and fever. Common (> 1/100 to < 1/10) side effects were redness at the injection site and nausea. Uncommon (> 1/1,000 to < 1/100) side effects were general malaise, insomnia, pain in the extremities, swollen lymph nodes and itching at the injection site. Rare (≥ 1/10,000 to < 1/1,000) side effects were acute peripheral facial palsy.
The most frequently observed local side effect was light to moderate pain at the injection site, which was reported by more than 80%, but more rarely among elderly people aged 55 years or more (71% after the first dose and 66% after the second dose) than among younger persons (83% after the first dose and 78% after the second dose). Among those who reported pain at the injection site following the first dose, an increased occurrence of local side effects was not recorded after the second dose. Conversely, redness as well as swelling were more frequent after the second than after the first injection. Generally, local reactions were light to moderate and of a short (1-2 days) duration.
The most frequent systemic side effects were fatigue and headache (59% and 52%, respectively, among younger participants below 55 years of age after the second dose, and 51% and 39%, respectively, among elderly participants after the second dose). Among systemic side effects, fever, fatigue, headache, chills, nausea, diarrhoea, muscle ache and joint ache occurred more frequently after the second than after the first vaccination.
Serious side effects were reported among less than 2% of all vaccine participants after each dose, apart from fatigue (3.8%) and headache (2%).
After use of Comirnaty® has been initiated, the US and Great Britain have observed a few cases of anaphylactic reactions. All vaccinations carry a small risk of a strong allergic reaction (anaphylaxis).
Special warnings and precautions for use
Anaphylaxis preparedness measures must be in place at all vaccination sites, and it falls upon the regional authorities to ensure this. Vaccination should be postponed in case of severe acute febrile (≥ 38.0 ⁰C) illness.
In its “Guidelines on the handling of COVID-19 vaccination ”(in Danish language), the Danish Health Authority assesses that vaccination should be given with caution to persons with thrombocytopenia and coagulation disorders as haemorrhage may occur following intramuscular injection in this group of patients. Persons in whom intramuscular injections in other conditions are contraindicated (e.g. persons with bleeding disorders) should not be vaccinated unless the potential benefits clearly outweigh the risk of administering the vaccine. Standard anticoagulative (AC) treatment is not normally a contraindication to intramuscular injection, and therefore standard AC treatment is also not a contraindication to vaccination.
The effect of the vaccine may be reduced in persons with a reduced immune response, including people who are receiving immunosupressive treatment. No data are available about concurrent administration of immunosupressants.
Clinical protection against SARS-CoV-2 cannot be guaranteed in all vaccinated persons, cf. the above section on the effect of the vaccine. No data are available on vaccination with Comirnaty® in persons who have received partial or full vaccination with another COVID-19 vaccine. You should therefore strive to always conclude vaccination with the same COVID-19 vaccine as that which was given at the first vaccination.
Hypersensitivity to any of the vaccine’s ingredients or excipients, please see the SPC. In particular, attention should be given to the ingredient polyethylene glycol (PEG) to which some (sensitized) persons may have serious allergic reactions.
Pregnancy and breast-feeding
Due to lacking safety data, the vaccine should not be given to pregnant women, and pregnancy should be excluded through pregnancy work-up before vaccinating women of fertile age. In case of amenorrhoea, the woman should be encouraged to take a pregnancy test before proceeding to vaccination, if relevant. If a woman has a non-acknowledged pregnancy at the time of her vaccination, termination of pregnancy is not recommended as the vaccine is not a live attenuated vaccine why no or only very limited foetal harm is expected.
It remains unknown if vaccine products may be found in breast milk. As a risk for the neonate cannot currently be excluded, the vaccine should not be given to breastfeeding women. Even so, if the mother is at risk of running a severe COVID-19 course, this should be considered as part of the overall risk assessment.
It remains unknown if the vaccine affects the fertility in men as well as women.
At present, the vaccine is only supplied to the regional vaccination centres established as part of the initiation of the COVID-19 vaccination programme. The vaccine is stored deep-frozen (-90 to -60 °C) at the SSI, and deep freezing should be maintained until thawing immediately prior to reconstitution.
The manufacturer has developed a transport solution, using dry ice, where each tray with 195 vials can be kept in deep freezing during transportation. This transport system, including a temperature logger, is reusable and must therefore be returned to the SSI once all vaccines have been administered. Even so, until local deep freezers are in place and have been validated, vaccines will be delivered from the SSI in freezer compartments.
Storage and handling
Locally, the vaccine is stored at min. -60 °C at which temperature it has a shelf life of approx. 6 months. Once removed from the freezer, the vaccine is thawed in a refrigerator for a minimum of three hours (when thawing in a tray with 195 vials). If a more rapid thawing is desirable, each individual vaccine vial may be thawed for 30 minutes at room temperature (max 30 °C). In the refrigerator, the thawed vaccine has a shelf life of five days at 2-8 °C.
Once removed from the refrigerator, the vials have a shelf life of max. two hours at up to 30 °C. Following reconstitution with a diluent (saline, see below), the reconstituted vaccine has a max. shelf life of 6 hours at up to 30 °C.
The vaccine contains no preservative.
Each vial contains 0.45 mL of liquid. Before reconstitution, the vaccine is off-white with no visible particles. Each vial must be diluted by adding 1.8 mL unpreserved isotonic saline (0.9%). This is removed from one of the provided 10 mL vials using a withdrawal needle (e.g. pink, 18G, however size 21 G is recommended by the manufacturer) mounted on a 2 mL syringe. Subsequently, any remaining diluent is discarded. Before dilution, the ampule is turned gently ten times. After dilution, 1.8 mL of air is drawn from the vaccine vial before the withdrawal needle is removed. Next, the reconstituted vaccine is gently turned another ten times. The SSI has prepared an infographic (in Danish language). For the Pfizer/BioNTech vaccine, the colour code is blue.
After reconstitution/dilution, the shelf life of the vaccine is max. six hours at up to 30 °C.
Dosage and administration
Following reconstitution, the multi-dose vial contains a total of 2.25 mL of reconstituted vaccine. Thus, a multi-dose vial contains an extra amount of vaccine to ensure that despite spillage when individual doses are drawn, the vial will contain sufficient vaccine for administration of five 0.3 mL vaccine doses. Despite the use of different needles and syringes that cause different vaccine spillage amounts, this excess vaccine ensures that there will always be five full doses of vaccine in the multi-dose vial.
A minimum of five 0.3 mL vaccine doses may be withdrawn from the reconstituted vaccine. Withdrawing into a 1 ml syringe may be done using the needle (normally G23, length 25-40 mm depending on the thickness of the subcutaneous tissue) also used for the subsequent injection. However, if spillage during withdrawal of the individual vaccine doses has been limited, one or two full additional 0.3 mL doses may remain in the multi-dose vial after withdrawal of the first five doses. If additional doses remain in the multi-dose vial, they may be withdrawn and used. If excess vaccine remains that does not correspond to a full extra dose (0.3 mL) in a vial, it must be discarded. A single dose may not be created by mixing several partial doses < 0.3 mL withdrawn from different vials.
The reconstituted vaccine (0.3 mL) is injected intramuscularly, normally in the deltoid muscle.
After vaccination, the Danish Health Authority recommends that the vaccinee remains in the waiting area for 15 minutes.
All COVID-19 vaccines, including any diluent, must be registered in the Danish Vaccination Register (DVR), either by rapid or standard registration. See separate instructions about this (in Danish language). The first vaccine supplies will be produced either for the US or the European market and therefore carry labels stating that this is the Pfizer-BioNtech COVID-Vaccine. Subsequently, the vaccine will be supplied in the approved European boxes under the name of Comirnaty®. These vaccines are identical (but the vaccines must be created under a separate vaccine ID in the DVR).
We encourage that the vaccination is registered as quickly as possible after the time of the vaccination. To ensure quality in the monitoring of the vaccines, it is important to ensure correct registration of product name and batch number.
Information for the person receiving the vaccination
The vaccinee should receive the folder published by the Danish Health Authority and prepared in collaboration with the Danish Medicines Agency (in Danish language). The folder provides information about the most frequently occurring side effects and informs that you should see your doctor if you experience any serious side effects.
Phone advice is also available via the joint corona hotline of the Danish authorities (+45 7020 0233). Phone advice does not include advice about symptoms or medical assessments in relation to citizens; for these complaints, please refer to your general practitioner.
Additional vaccination to the person giving the vaccination
Vaccinators may find additional information about COVID-19 vaccination (in Danish language) at the websites of the Danish Health Authority , the Danish Medicines Agency and Statens Serum Institut. At the SSI’s website, the following are available for download: the vaccine-specific description for Comirnaty® and infographics about vaccine facts and about storage and reconstitution/injection of the vaccine (all in Danish language). This material will also be enclosed with each batch of vaccines supplied by the SSI.
The SSI has prepared a questions and answers section about COVID-19 vaccination (in Danish language) at our COVID-19 subsite for use by healthcare workers.
If the need arises for further vaccination-related advice, healthcare workers may contact the Department of Infectious Disease Epidemiology and Prevention. We are open for phone-based advice at +45 3268 3037, from Monday to Friday 8.30-11.00 a.m., except for Wednesdays 12.30-3.00 p.m. Beyond these periods, the department can be contacted during daytime office hours on phone +45 3268 3038. You may also write to email@example.com. On working days, we aim to respond within the day the request was made, but we cannot guarantee that this is possible in all cases. Outside normal office hours, the physician on call may be contacted for acute advice on phone +45 4131 7404.
(P. H. Andersen, L. K. Knudsen, P. Valentiner-Branth, Department of Infectious Disease Epidemiology and Prevention)