No 6 - 2021

Vaccination against COVID-19 - COVID-19 Vaccine AstraZeneca^®

On 29 January 2021, the third vaccine against COVID-19 was authorised by the EU Commission following the recommendation of the European Medicines Agency (EMA). The vaccine is manufactured by AstraZeneca and marketed under the name of ”COVID-19 Vaccine AstraZeneca” or ”COVID-19 vaccine (ChAdOx1-S [recombinant])”. Below, we use the first of the two terms.

The vaccines are supplied to Statens Serum Institut (SSI) and the first batch consists of approx. 24,000 doses, which reached the SSI on 6 February 2021. The vaccines will be released and distributed to the Danish regions on 8 February. Another batch containing the same number of doses was confirmed for delivery towards the end of week 6, and we expect to receive a higher number of doses in late February and early March.

The AstraZeneca vaccine will form part of the COVID-19 vaccination scheme in line with the two currently used vaccines from Pfizer/BioNTech and Moderna. 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. It is not possible to chose which vaccine you want to give or receive.

The EU Commission has authorised the vaccine COVID-19 Vaccine AstraZeneca® for everyone aged 18 years or more. In the initial trials, only a minor share (13%) of the people vaccinated in the primary efficacy population were older than 55 years, and sufficient data are therefore not yet available to assess the clinical protection/efficacy in this group.

Furthermore, in the 56-65 years age group, the difference between the observed number of COVID-19 cases among vaccinated patients and controls was too small to draw firm conclusions about the effect of COVID-19 Vaccine AstraZeneca® in this age group. Even so, measurements of antibodies against the vaccine antigen/SARS-CoV-2 show that elderly people (above 56 years of age) do form considerable amounts of antibodies, even though the levels are lower than those recorded among younger vacinees. Even though the threshold level providing protection against clinical infection currently remains unknown, EMA has assessed that these immunogenicity data form a sufficient base for a (conditional) authorisation with no upper age limit.

Even so, the Danish Health Authority (in line with the authorities of a range of other countries) has assessed that, when possible and until more data on the effect among elderly people become available, COVID-19 Vaccine AstraZeneca^® should be prioritised for persons below 65 years of age who are not at increased risk of running a severe COVID-19 disease course. In special cases, e.g., when other COVID-19 vaccines cannot be used, persons not belonging to this group may also be offered vaccination with COVID-19 Vaccine AstraZeneca^®.

In line with the other authorised COVID-19 vaccines, the COVID-19 Vaccine AstraZeneca^® has been granted a conditional marketing authorisation in the EU. This means that AstraZeneca is required continuously to report collected data to the EMA, and that the vaccine is monitored just like the COVID-19 Vaccine Moderna® and the Comirnaty^® vaccine - read more about this topic in EPI-NEWS no 51/52b 2020. To achieve a standard marketing authorisation, the manufacturer must continuously report data from the clinical phase-3 trial. A description of the post-marketing studies that the manufacturer has an obligation to complete is provided in the so-called risk-management plan.

Information about the basis for the authorisation, product information, patient information leaflets, etc. is available at the website of the Danish Medicines Agency.

About the COVID-19 Vaccine AstraZeneca^®

COVID-19 Vaccine AstraZeneca^® is based on a known vaccine technology and employs an adenovirus vector that enhances the immune response. (In the development phase, the vaccine candidate was coined AZD1222). The vector is a non-replicating chimpanzee adenovirus (ChAdOx1) containing the genetic code for the spike protein located on the surface of new corona virus (SARS-CoV-2). The vector is absorbed by the cells where it releases the coding DNA into the nucleus of the cell and mRNA is produced, which is then transported out of the cell core and translated to spike protein. The protein and protein fragments are subsequently presented on the surface of the cell and will therefore activate the immune system of the vaccinee, thereby inducing the production of protective antibodies and releasing a specific cellular (T-cell mediated) immune response.

The vaccine is authorised for use in persons aged 18 years or more, and is supplied ready for use - i.e. must not be diluted. Each vial includes a minimum of ten 0.5 mL doses, and each dose contains no less than 5x10⁸ virus particles.

The COVID-19 Vaccine AstraZeneca^® vaccination scheme consists of two 0.5 mL doses administered at a 28-day interval. Even so, a minimum period of 26 days is acceptable. Exceptionally, the second dose may be planned for administration no later than on day 84.

Efficacy of the vaccine

COVID-19 Vaccine AstraZeneca^® was tested in clinical trials, and its efficacy was assessed in an analysis of preliminary data collected from four studies; two phase-1/2 studies, one phase-2/3 study (Great Britain) and one phase-3 study (Brazil). In the overall analysis, a total of 6,106 persons received two doses of COVID-19 Vaccine AstraZeneca^®, whereas 6,090 persons received two doses of active control or placebo (meningococcal vaccine or saline) at a 3-23-week interval. In the primary efficacy analysis, a total of 86% of the participants received the second injection within 4-12 weeks (28-84 days). More than 14 days after the second vaccination, a total of 64 cases of laboratory-verified COVID-19 occurred in the vaccine group (n=5,258) and 154 cases in the control group (n=5,210), corresponding to a 59.5% vaccine efficacy (95% confidence interval 45.8%-69.7%). The efficacy was comparable among study participants who had comorbidities at baseline. Among study participants receiving two doses at a 3-23-week interval, the efficacy of the secondary efficacy analysis was 62.6% (95% confidence interval 50.9%-71.5%).

Assessed based on limited data, the vaccine seems to protect against admission to hospital which may serve as a proxy for a serious COVID-19 course. In the vaccine group of the phase-three trial, no patients were admitted as from 22 days after the first dose, compared with 14, including one fatality, in the control group. Among participants receiving two doses, there were no admitted patients in the vaccine group from 15 days after the second dose compared with eight in the control group, including one case of severe COVID-19 disease.

Who may receive the vaccine?

Persons aged 18 years or more to achieve active protection against SARS-CoV-2. Even so, the Danish Health Authority has assessed that, when possible and until more data on the effect among elderly people become available, COVID-19 Vaccine AstraZeneca^® should be prioritised for persons below 65 years of age who are not at increased risk of running a severe COVID-19 disease course.

For contraindications and precautions, please see below.

Side effects

The safety profiles of COVID-19 Vaccine AstraZeneca^® were studied in the clinical trials. Here, 23,745 persons were followed, 12,021 of whom received at least one dose of COVID-19 Vaccine AstraZeneca^®.

The most frequently observed side effects were tenderness at the injection site (63.7%), pain at the injection site (54.2%), headache and fatigue (approx. 53%), myalgia and malaise (44%), fever (33.6%) and chills (31.9%), arthralgia (26.4%) and nausea (21.9%).

Most of the side effects were mild to moderate and receded after few days. In the vaccine group, 0.7% experienced serious side effects, whereas this was the case for 0.8% of the persons in the control group.

Reactogenicity was generally lighter and was reported less frequently in adults (≥65 years).

All vaccinations carry a small risk of a strong allergic reaction (anaphylaxis).

For the remaining reported side effects, please see the summary of product characteristics (SPC) for the vaccine and the published phase-2/3 and phase-3 trial.

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. After vaccination, at least 15 minutes of close monitoring is recommended. The second dose should not be given to people who have experienced anaphylaxis in connection with vaccination with the first dose of COVID-19 Vaccine AstraZeneca^®.
Vaccination should be postponed in case of severe acute febrile (≥38.0°C) illness.

Persons who have experienced an immediate anaphylactic reaction after receiving other vaccinations or after having another medicinal product injected should be assessed by a physician before being vaccinated with COVID-19 vaccines as they are at increased risk of experiencing an allergic reaction. These patients may be assessed by their GP, who may confer with a specialised allergy centre as needed. Particular attention should be given to persons who may have undiagnosed allergy to the ingredient polyethylene glycol (PEG). COVID-19 Vaccine AstraZeneca^® does not contain PEG but does contain polysorbate 80, and cross-allergenicity has been observed for these two substances.

It must be assessed if vaccination of these persons requires specially enhanced anaphylactic preparedness measures at a hospital department with relevant experience.

Persons with mastocytosis must be vaccinated in the specialised national treatment centre (Dermatology Department I and the Allergy Centre at Odense University Hospital), which is responsible for contact to these patients.

In its Guideline on the handling of COVID-19 vaccination (Danish language, published on 5 February 2021), the Danish Health Authority assesses that vaccination should be given with caution to persons with thrombocytopenia (< 10 x 10⁹/L ) and coagulation disorders. In these cases, special needles should be used (e.g. size 25-27 G) as haemorrhage may occur following intramuscular injection in this group of patients. No restrictions apply for intramuscular vaccination of patients with a thrombocyte count ≥ 10 x 10⁹/L.

Patients with severe or moderate haemophilia A or B or severe von Willebrand’s disease may be vaccinated intramuscularly if they have received prophylactic treatment with a factor product a few hours before their vaccination. Patients with milder haemophilia must contact their haemophilia centre to establish if they should receive prophylactic haemophilia medicine before being vaccinated. 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 efficacy of the vaccine may be reduced in persons with a reduced immune response, including people who are receiving immunosuppressive treatment. The Danish Health Authority’s guideline refers to recommendations prepared by medicinal societies about the timing of vaccination for patients who are receiving chemotherapy, patients receiving immuno-suppressants (e.g. anti-CD 20 antibodies) and patients who have received immune therapy (and who may have immune activation), etc.

Clinical protection against SARS-CoV-2 cannot be guaranteed in all vaccinated persons, cf. the above section on the efficacy of the vaccine.

No data are available on vaccination with the COVID-19 Vaccine AstraZeneca^® in persons who have received partial or full vaccination with another COVID-19 vaccine. It is therefore important to always conclude vaccination with the same COVID-19 vaccine as that which was given at the first vaccination.

Contraindication

For hypersensitivity to any of the vaccine’s ingredients or excipients, please see the summary of product characteristics.

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.

The vaccine is not expected to affect the fertility of either men or women. Animal studies have shown no vaccine-related effects on female fertility or pregnancy.

Dispensing

COVID-19 Vaccine AstraZeneca^® is supplied only to the regional vaccination centres established as part of the initiation of the COVID-19 vaccination programme. The vaccine is kept in refrigerated storage at the SSI (2-8 °C) and must be kept cool until immediately before being used. Each pack contains ten vials each containing a minimum of ten doses.

Storage and handling

COVID-19 Vaccine AstraZeneca^® is supplied refrigerated (2-8 °C) and has a shelf life of six months at this temperature.
Once opened, the vaccine remains usable for six hours at 2-30 °C and for 48 hours at 2-8 °C. The vial may be returned to the refrigerator once, but the total storage period after opening must not exceed 48 hours (including any time stored at room temperature).

Store in the original package to protect from light and do not freeze.

Preparation

The vaccine is provided ready to use. The vaccine is a colourless to slightly brown solution and transparent to slightly opaque solution. Inspect the vaccine visually before use; if visible particle discolouration is observed, the vaccine must be discarded. 0.5 mL of vaccine is withdrawn into the syringe and injected. Changing the needle between withdrawal from the vial and injection is unnecessary. The SSI has prepared an infographic.

According to the EU SPC, a total of ten 0.5 mL doses may be drawn from the vial, and any unused vaccine solution must be discarded as usual and no later than 48 hours after its preparation if stored in a refrigerator, and no later than six hours after being prepared if stored at room temperature. State the date and time of first use on the vial to avoid unintended events.

Dosage and administration

COVID-19 Vaccine AstraZeneca^® is a ready-to-use multidose vial that should not be diluted. Each vial includes 6.5 mL corresponding to at least ten 0.5 mL doses each containing no less than 5×10⁸ virus particles.

Two 0.5 mL doses of undiluted vaccine are administered at a 28-day interval. If the second vaccine is given a minimum of 26 days after the first vaccination, this may be accepted as valid vaccination. If the second dose is not administered on day 28, it should be given as soon as possible thereafter and should not be planned for administration after day 84 (12 weeks).

If the second dose of COVID-19 Vaccine AstraZeneca^® is administered less than 26 days after the first dose, the initial dose must be disregarded, and an extra (third) dose must be given no less than 28 days after the dose that was administered too early.

Immunisation is done by intramuscular injection into the deltoid muscle. In case of contraindication to vaccination in the deltoid muscle, the vaccine may be administered to the central section of the lateral great muscle.

If the vaccination series is initiated using COVID-19 Vaccine AstraZeneca^®, it is important that it is completed using the same vaccine type, as experience with the interchangeability of COVID-19 vaccines is lacking.

Observation

After vaccination, the Danish Health Authority recommends that the vaccinee remains in the waiting area for a minimum of 15 minutes.

Registration

All COVID-19 vaccines must be registered in the Danish Vaccination Register (DVR), either by rapid or standard registration. See separate instructions about this.
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/lot 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. 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/symptoms after being vaccinated.

Phone advice is also available to the general public via the joint corona hotline of the Danish authorities at +45 7020 0233. Phone advice does not include advice about symptoms or medical assessments in relation to citizens; these complaints should be referred to the general practitioner.

Additional vaccination to the person giving the vaccination

Vaccinators may find additional information about COVID-19 vaccination 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 descriptions and infographics about vaccine facts  and about storage  and reconstitution/injection of the vaccines (all in Danish).

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 at our COVID-19 subsite for use by healthcare workers (in Danish). Please also refer to the Knowledge bank of the Danish Health Authority for answers to frequently asked questions.

If the need arises for 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 covidinfo@ssi.dk. 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.

(K.F. Nielsen, L.K. Knudsen, P. Valentiner-Branth, P.H. Andersen, Department of Infectious Disease Epidemiology and Prevention)