Coronavirus vaccine – weekly summary of Yellow Card reporting

By Medicines & Healthcare products Regulatory Agency

At the time of this report, over 127,000 people across the UK have died within 28 days of a positive test for coronavirus (COVID-19).

Vaccination is the single most effective way to reduce deaths and severe illness from COVID-19. A national immunisation campaign has been underway since early December 2020.

Three COVID-19 vaccines, Pfizer/BioNTech, Oxford University/AstraZeneca and Moderna vaccines, are currently being used in the UK. All have been authorised for supply by the Medicines and Healthcare products Regulatory Agency (MHRA) following a thorough review of safety, quality and efficacy information from clinical trials. In clinical trials, the vaccines showed very high levels of protection against symptomatic infections with COVID-19. Data are now available on the impact of the vaccination campaign in reducing infections and illness in the UK.

All vaccines and medicines have some side effects. These side effects need to be continuously balanced against the expected benefits in preventing illness.

The Pfizer/BioNTech vaccine was evaluated in clinical trials involving more than 44,000 participants. The most frequent adverse reactions in trials were pain at the injection site, fatigue, headache, myalgia (muscle pains), chills, arthralgia (joint pains), and fever; these were each reported in more than 1 in 10 people. These reactions were usually mild or moderate in intensity and resolved within a few days after vaccination. Adverse reactions were reported less frequently in older adults (over 55 years) than in younger people.

The Oxford University/AstraZeneca vaccine was evaluated in clinical trials involving more than 23,000 participants. The most frequently reported adverse reactions in these trials were injection-site tenderness, injection-site pain, headache, fatigue, myalgia, malaise, pyrexia (fever), chills, arthralgia, and nausea; these were each reported in more than 1 in 10 people. The majority of adverse reactions were mild to moderate in severity and usually resolved within a few days of vaccination. Adverse reactions reported after the second dose were milder and reported less frequently than after the first dose. Adverse reactions were generally milder and reported less frequently in older adults (65 years and older) than in younger people.

The Moderna vaccine was evaluated in clinical trials involving more than 30,000 participants. The most frequent adverse reactions in these trials were pain at the injection site, fatigue, headache, myalgia (muscle pains), arthralgia (joint pains), chills, nausea/vomiting, axillary swelling/tenderness (swelling/tenderness of glands in the armpit), fever, injection site swelling and redness; these were each reported in more than 1 in 10 people. These reactions were usually mild or moderate in intensity and resolved within a few days after vaccination. Adverse reactions were reported less frequently in older adults (over 65 years) than in younger people.

The MHRA’s role is to continually monitor safety during widespread use of a vaccine. We have in place a proactive strategy to do this. We also work closely with our public health partners in reviewing the effectiveness and impact of the vaccines to ensure the benefits continue to outweigh any possible side effects.

Part of our monitoring role includes reviewing reports of suspected side effects. Any member of the public or health professional can submit suspected side effects through the Yellow Card scheme. The nature of Yellow Card reporting means that reported events are not always proven side effects. Some events may have happened anyway, regardless of vaccination. This is particularly the case when millions of people are vaccinated, and especially when most vaccines are being given to the most elderly people and people who have underlying illness.

This safety update report is based on detailed analysis of data up to 21 April 2021. At this date, an estimated 11.2 million first doses of the Pfizer/BioNTech vaccine and 22 million first doses of the Oxford University/AstraZeneca vaccine had been administered, and around 6.8 million and 4.4 million second doses of the Pfizer/BioNTech vaccine and Oxford University/AstraZeneca vaccine respectively. An approximate 0.1 million first doses of the Moderna vaccine have also now been administered.

As of 21 April 2021, for the UK, 52,130 Yellow Cards have been reported for the Pfizer/BioNTech vaccine, 153,098 have been reported for the Oxford University/AstraZeneca vaccine, 228 for the Moderna vaccine and 541 have been reported where the brand of the vaccine was not specified.

For the Pfizer/BioNTech and Oxford University/AstraZeneca vaccines the overall reporting rate is around 3 to 6 Yellow Cards per 1,000 doses administered.

In the week since the previous summary for 14 April 2021 we have received a further 2,108 Yellow Cards for the Pfizer/BioNTech vaccine, 7,104 for the Oxford University/AstraZeneca vaccine, 184 for the Moderna vaccine and 25 where the brand was not specified.

It is important to note that Yellow Card data cannot be used to derive side effect rates or compare the safety profile of COVID-19 vaccinations as many factors can influence ADR reporting.

For all COVID-19 vaccines, the overwhelming majority of reports relate to injection-site reactions (sore arm for example) and generalised symptoms such as ‘flu-like’ illness, headache, chills, fatigue (tiredness), nausea (feeling sick), fever, dizziness, weakness, aching muscles, and rapid heartbeat. Generally, these happen shortly after the vaccination and are not associated with more serious or lasting illness.

These types of reactions reflect the normal immune response triggered by the body to the vaccines. They are typically seen with most types of vaccine and tend to resolve within a day or two. The nature of reported suspected side effects is broadly similar across age groups, although, as was seen in clinical trials and as is usually seen with other vaccines, they may be reported more frequently in younger adults.

Severe allergy

On 9 December 2020, the MHRA issued preliminary guidance on severe allergic reactions after the Pfizer/BioNTech vaccine due to early reports of anaphylaxis. Following further detailed review, this advice was amended on 30 December to the current advice. This advice is that people with a previous history of severe allergic reactions to any ingredients of the vaccine should not receive it. People who receive the vaccine should be monitored for at least 15 minutes afterwards.

Widespread use of the vaccine now suggests that severe allergic reactions to the Pfizer/BioNTech vaccine are very rare. Anaphylaxis can also be a very rare side effect associated with most other vaccines.

Following very substantial exposure across the UK population, no other new safety concerns have been identified from reports received so far.

Blood clots with concurrent low platelets

The MHRA has undertaken a thorough review into UK reports of an extremely rare specific type of blood clot in the brain, known as cerebral venous sinus thrombosis (CVST) occurring together with low levels of platelets (thrombocytopenia) following vaccination with the COVID-19 Vaccine AstraZeneca. It is also considering other blood clotting cases (thromboembolic events) alongside low platelet levels.

On the basis of this ongoing scientific review, it has concluded that the evidence of a link with COVID-19 Vaccine AstraZeneca is stronger, but more work is still needed. An announcement on 7 April 2021 gave information about cases received up to 31 March 2021. In this report (page 13) we provide updated information on cases received up to 21 April 2021. Our advice remains unchanged.

Anyone who experienced cerebral or other major blood clots occurring with low levels of platelets after their first vaccine dose of COVID-19 Vaccine AstraZeneca should not have their second dose. Anyone who did not have these side effects should come forward for their second dose when invited.

The MHRA recently confirmed that the evidence to date does not suggest that the COVID-19 Vaccine AstraZeneca causes venous thromboembolism without a low platelet count.

If you experience any of the following from around 4 days after vaccination you should seek medical advice urgently:

• a severe headache that is not relieved with simple painkillers or is getting worse or feels worse when you lie down or bend over
• an unusual headache that may be accompanied by blurred vision, confusion, difficulty with speech, weakness, drowsiness or seizures (fits)
• rash that looks like small bruises or bleeding under the skin beyond the injection site
• shortness of breath, chest pain, leg swelling or persistent abdominal (tummy) pain.

Conclusion

• Vaccines are the best way to protect people from Covid-19 and have already saved thousands of lives. Everyone should continue to get their vaccination when asked to do so unless specifically advised otherwise.
• As with all vaccines and medicines, the safety of COVID-19 vaccines is being continuously monitored .
• Cases of an extremely rare specific type of blood clot with low blood platelets continue to be investigated.

Further information on the type of suspected adverse reactions (ADRs) reported for the COVID-19 mRNA Pfizer/BioNTech vaccine, the COVID-19 Oxford University/AstraZeneca vaccine and the COVID-19 Moderna vaccine is provided in Annex 1. It is important to read the attached guidance notes to ensure appropriate interpretation of the data.

1. Introduction

The MHRA is the executive Agency of the Department of Health and Social Care that acts to protect and promote public health and patient safety, by ensuring that medicines and medical devices meet appropriate standards of safety, quality and efficacy.

The MHRA operates the Yellow Card scheme on behalf of the Commission on Human Medicines (CHM). The scheme collects and monitors information on suspected safety concerns or incidents involving vaccines, medicines, medical devices, and e-cigarettes. The scheme relies on voluntary reporting of suspected adverse incidents by healthcare professionals and members of the public (patients, users, or carers). The purpose of the scheme is to provide an early warning that the safety of a product may require further investigation. Further information about the Yellow Card scheme, including its contribution to identifying safety issues can be found on the Yellow Card website.

The MHRA has played an active role in responding to the coronavirus pandemic. In relation to COVID-19 vaccines, the MHRA has authorised their supply following a rigorous review of their safety, quality and efficacy. The clinical trials of COVID-19 vaccines have shown them to be effective and acceptably safe; however, as part of its statutory functions, the MHRA is responsible for monitoring these vaccines on an ongoing basis to ensure their benefits continue to outweigh any risks. This is a requirement for all authorised medicines and vaccines in the UK. This monitoring strategy is continuous, proactive and based on a wide range of information sources, with a dedicated team of scientists reviewing information daily to look for safety issues or unexpected rare events.

This report summarises information received via the Yellow Card scheme and will be published regularly to include other safety investigations carried out by the MHRA under the COVID-19 Vaccine Surveillance Strategy.

What is a Yellow Card?

The Yellow Card scheme is a mechanism by which anybody can voluntarily report any suspected adverse reactions or side effects to the vaccine. It is very important to note that a Yellow Card report does not necessarily mean the vaccine caused that reaction or event. We ask for any suspicions to be reported, even if the reporter isn’t sure if it was caused by the vaccine. Reports to the scheme are known as suspected adverse reactions (ADRs).

Many suspected ADRs reported on a Yellow Card do not have any relation to the vaccine or medicine and it is often coincidental that they both occurred around the same time. The reports are continually reviewed to detect possible new side effects that may require regulatory action, and to differentiate these from things that would have happened regardless of the vaccine or medicine being administered, for instance due to underlying or undiagnosed illness.

It is therefore important that the suspected ADRs described in this report are not interpreted as being proven side effects of COVID-19 vaccines. A list of the possible side effects of COVID-19 mRNA Pfizer/BioNTech, COVID-19 AstraZeneca vaccine and COVID-19 Moderna vaccine is provided in the product information document for healthcare professionals and the UK recipient information. These can also be found on the Coronavirus Yellow Card reporting site.

This public summary provides an overview of all UK suspected ADRs associated with the new coronavirus (COVID-19) vaccines (COVID-19 mRNA Pfizer/BioNTech, COVID-19 Oxford University/AstraZeneca vaccine and COVID-19 vaccine Moderna), and MHRA’s analysis of the data, between 9 December 2020 and 21 April 2021 (inclusive). A glossary of key terms is provided in Annex 2.

If identified, information on new and emerging safety concerns will be provided in future editions of this report together with details of any resulting regulatory action or changes to advice on use of the vaccines.

2. Yellow Card reports

Vaccine doses administered

Data from the UK Public Health agencies show that at least 33,257,651 people have received their first vaccination in the UK by 21 April 2021, with 11,192,601 second doses administered. The current priority groups of the immunisation campaign include people over the age of 45 years, the clinically vulnerable, care home residents and workers, and frontline health and social care workers.

Table 1: Number of people who have received the first dose of a vaccination for COVID-19 in the UK between 8 December 2020 and end of 21 April 2021.

Table 2: Number of people who have received the second dose of a vaccination for COVID-19 in the UK between 8 December 2020 and end of 21 April 2021.

As of 21 April, an estimated 11.2 million first doses of the Pfizer/BioNTech vaccine and 22.0 million first doses of the Oxford University/AstraZeneca vaccine, and 0.1 million first doses of the Moderna vaccine had been administered, and around 6.8 million and 4.4 million second doses of the Pfizer/BioNTech vaccine and Oxford University/AstraZeneca vaccine respectively.

The estimated number of doses administered differs from the estimated number of people vaccinated due to the different data sources used.

Yellow Card reporting trends

A report of a suspected ADR to the Yellow Card scheme does not necessarily mean that it was caused by the vaccine, only that the reporter has a suspicion it may have. Underlying or previously undiagnosed illness unrelated to vaccination can also be factors in such reports. The relative number and nature of reports should therefore not be used to compare the safety of the different vaccines. All reports are kept under continual review in order to identify possible new risks.

Up to and including 21 April 2021, the MHRA received and analysed 52,130 UK Yellow Cards from people who have received the COVID-19 mRNA Pfizer/BioNTech vaccine. These reports include a total of 149,082 suspected reactions (i.e. a single report may contain more than one symptom). The first report was received on 9 December 2020.

Up to and including 21 April 2021, the MHRA received and analysed a total of 153,098 UK reports of suspected ADRs to the COVID-19 Oxford University/AstraZeneca vaccine. These reports include a total of 573,650 suspected reactions (a single report may contain more than one symptom). The first report was received on 4 January 2021.

Up to and including 21 April 2021, the MHRA received and analysed a total of 228 UK reports of suspected ADRs to the COVID-19 Moderna vaccine. These include a total of 660 suspected reactions (a single report may contain more than one symptom). The first report was received on 7 April 2021.

Additionally, up to and including 21 April 2021, the MHRA received 541 Yellow Card reports where the brand of vaccine was not specified by the reporter.

In the week since the previous summary for 14 April 2021 we have received a further 2,108 Yellow Cards for the Pfizer/BioNTech vaccine, 7,104 for the Oxford University/AstraZeneca vaccine, 184 for the Moderna vaccine and 25 where the brand was not specified.

It is important to note that Yellow Card data cannot be used to derive side effect rates or compare the safety profile of COVID-19 vaccinations as many factors can influence ADR reporting.

Table 3: Number of suspected ADR reports received in the UK up to and including 21 April 2021.

The figures in table 3 are based upon the postcode provided by the reporter. The sums of the reports in the table will not equal the total reports received for each vaccine as postcode may not have always been provided or may have been entered incorrectly. It is important to note that the number of reports received for each country does not directly equate to the number of people who may have experienced adverse reactions and therefore cannot be used to determine the incidence of reactions. ADR reporting rates are influenced by many aspects, including the extent of use.

We are working with public health bodies and encouraging all healthcare professionals and patients alike to report any suspected ADRs to the Yellow Card scheme. As expected, reports gradually increase in line with an increase in doses administered.

The overall reporting rate is in the order of 3 to 6 Yellow Cards per 1,000 doses administered for the Pfizer/BioNTech and Oxford University/AstraZeneca vaccines. It is known from the clinical trials that the more common side effects for both vaccines can occur at a rate of more than one in 10 doses (for example, local reactions or symptoms resembling transient flu-like symptoms).

3. Analysis of data

One of the MHRA’s main roles is to continually monitor safety of medicines and vaccines during widespread use, and we have in place a proactive strategy to do this for COVID-19 vaccines. We also work closely with our public health partners in reviewing the effectiveness and impact that the vaccines are having to ensure benefits continue to outweigh any possible side effects. In addition, we work with our international counterparts to gather information on the safety of vaccines in other countries.

Given the huge scale of the COVID-19 immunisation programme, with many millions of doses of vaccine administered over a relatively short time period, vigilance needs to be continuous, proactive and as near real-time as is possible. The importance of this is two-fold. First we need to rapidly detect, confirm, and quantify any new risks and weigh these against the expected benefits. We then can take any necessary action to minimise risks to individuals.

Secondly, we need to very quickly establish if any serious medical events which are temporally-related to vaccination are merely a coincidental association. These associations are likely while we are still in the midst of a national epidemic, and because many of the millions of people offered the vaccine in the early phase of a vaccination campaign are elderly and/or have underlying medical conditions, which increases the likelihood of unrelated illnesses occurring soon after vaccination. As mentioned above, the nature of Yellow Card reporting means that reported events are not always proven adverse reactions, and some may have happened regardless of vaccination.

Yellow Card reports of suspected ADRs are evaluated, together with additional sources of evidence, by a team of safety experts to identify any new safety issues or side effects. We apply statistical techniques that can tell us if we are seeing more events than we would expect to see, based on what is known about background rates of illness in the absence of vaccination. This aims to account for factors such as coincidental illness. We also look at the clinical characteristics to see if new patterns of illness are emerging that could indicate a new safety concern.

We supplement this form of safety monitoring with other epidemiology studies including analysis of data on national vaccine usage, anonymised GP-based electronic healthcare records and other healthcare data to proactively monitor safety. These combined safety data enable the MHRA to detect side effects or safety issues associated with COVID-19 vaccines. As well as confirming new risks, an equally important objective of monitoring will be to quickly rule out risks – in other words to confirm that the vaccine is not responsible for a suspected side effect and to provide reassurance on its safety and this is discussed below.

We also take into account the international experience based on data from other countries using the same vaccines.

Overall safety

As with any vaccine, the COVID-19 vaccines will cause side effects in some people. The total number and the nature of Yellow Cards reported so far is not unusual for a new vaccine for which members of the public and healthcare professionals are encouraged to report any suspected adverse reaction.

As highlighted above, it is known from the clinical trials that the most common side effects for both vaccines can occur at a rate of more than one per 10 doses (such as local reactions, symptoms resembling transient flu-like symptoms). Overall, Yellow Card reporting is therefore lower than the reporting rate of possible side effects from the clinical trials, although we generally do not expect all suspected side effects to be reported on Yellow Cards. The primary purpose of Yellow Card reporting is to detect new safety concerns.

For all vaccines, detailed review of all reports has found that the overwhelming majority relate to injection site reactions (sore arm for example) and generalised symptoms such as a ‘flu-like’ illness, headache, chills, fatigue (tiredness), nausea (feeling sick), fever, dizziness, weakness, aching muscles, and rapid heartbeat. Generally, these happen shortly after the vaccination and are not associated with more serious or lasting illness. These types of reaction reflect the acute immune response triggered by the body to the vaccines, are typically seen with most types of vaccine and tend to resolve within a day or two. The nature of reported suspected ADRs across all ages is broadly similar, although, as seen in the clinical trials and as is usually seen with other vaccines, they may be reported more frequently in younger adults.

As we receive more reports of these types of reactions with more exposure to the COVID-19 vaccines, we are building a picture of how individuals are experiencing them and the different ways that side effects may present in people. Some people have reported a sudden feeling of cold with shivering/shaking accompanied by a rise in temperature, often with sweating, headache (including migraine-like headaches), nausea, muscle aches and feeling unwell, starting within a day of having the vaccine. Similar to the flu like illness reported in clinical trials, these effects may last a day or two.

It is important to note that it is possible to have caught COVID-19 and not realise until after vaccination. If other COVID symptoms are experienced or fever is high and lasts longer than two or three days, vaccine recipients should stay at home and arrange to have a test.