- Vaccine safety is assessed in clinical trials before a vaccine is approved by regulators for wider use.
- Safety monitoring continues once a vaccine is approved. This is to detect rare side effects and to monitor safety in groups of people who may not have been included in clinical trials that may be at a higher risk of experiencing side effects.
- As with any medicine, side effects can result from vaccines. These can be directly related to the vaccine, or other ingredients in the vaccine formulation. Others may be related to the process of immunisation – for example incorrect preparation or poor vaccination technique. Others may occur but be purely coincidental and are unrelated to the vaccine.
- Vaccine safety is continuously monitored using information from a number of sources. This includes real-time reporting of reactions, called adverse events, in a national system called the Yellow Card Scheme.
- Analysis of reported adverse events determines why and how often they occur and what action is needed to reduce any risks. It also determines which are real side effects from those which are unrelated to the vaccine.
- The Medicines and Healthcare products Regulatory Agency (MHRA) is the body responsible for medicines (including vaccine) safety. It acted within 24 hours to revise guidance on the use of the Pfizer/BioNTech COVID-19 vaccine following reports of three people experiencing allergic reactions on 8 December.
As with any new medicine, once a vaccine has been approved for use in people, data are continuously collected and monitored to improve knowledge about its safety profile. This article explains which data are collected, how the vaccine is monitored and by whom. It also discusses which people and organisations are responsible for this process and what happens if there are concerns about a vaccine’s safety.
This process is called pharmacovigilance and applies to any medicine. It includes all the activities to detect, assess, understand and prevent adverse events from all medicines, including vaccines. Unintended effects that may be linked to medicines are called adverse drug reactions, adverse events or undesirable effects. For vaccines they are sometimes referred to as adverse events following immunisation (AEFIs). Side effects are unwanted effects that occur during use of a drug or vaccine, such as pain at the injection site of a vaccine.
Assessing vaccine safety
Like any new medicine, vaccines are developed and tested in clinical trials. These trials comprise different stages to find out if they work and if they are safe to use in people. The clinical development of a vaccine takes place in four stages called phases. Safety monitoring takes place in all phases, including after a vaccine has been approved for use in people.
A small group of healthy people (<100) is given the vaccine to make sure there are no safety concerns, to see how well it stimulates an immune response and to work out an effective dose.
The vaccine is tested in a larger group (several hundred people) to see whether the vaccine works consistently, to assess the immune response and to look for side effects and adverse events.
The vaccine is studied on a much larger scale (several thousand people) under natural disease conditions. This produces enough data to identify rare side effects and adverse events and to evaluate how well the vaccine works in the real world; does it generate enough immunity to prevent and reduce disease?
Between phases 3 and 4 manufacturers apply for a license from regulators so that their vaccine can be marketed for human use. Experts review all the data to see whether the vaccine works to the standards required for both safety and its efficacy in reducing disease.
After licensing, research continues to monitor any adverse effects and to determine long-term effectiveness. This activity is called pharmacovigilance or post-marketing surveillance.
What is pharmacovigilance and how does it work for vaccines?
Pharmacovigilance describes all the activities to detect, assess, understand and prevent adverse events from all medicines, including vaccines.
This process begins in clinical trials using well-established safety protocols. It is not uncommon for a vaccine trial to be paused if there is a report of a serious adverse event. This allows investigators to investigate possible causes and then decide whether the trial should continue. Here are two examples of how this process worked for new COVID-19 vaccines in development:
- Janssen / Johnson & Johnson adenovirus-based vaccine. The phase 3 trial was paused for a few days following a serious medical event in one of the participants. There was no evidence that it was related to the vaccine and the trial resumed.
- Oxford University / AstraZeneca adenovirus-based vaccine. An unexplained illness in the UK arm of the phase 3 trial led to a pause of all the phase 3 trials in progress internationally. This was not considered to be linked to the vaccine and trials resumed a few days later.
Once a medicine is used in the general population more data can be collected about how it works in people. This expands on the evidence that is collected when a medicine is being developed and tested by a manufacturer in phases 1–3 of clinical trials.
For a vaccine, continued data collecting can tell us more about its ability to reduce the transmission of an infectious disease. It also tells us more about its impact on the number and severity of infections in people from different age groups, or groups that share other characteristics, such as ethnicity or underlying medical conditions.
Importantly, more data are collected about safety. This is to reveal any adverse events or side effects that may be so rare (for example 1 in 500,000 people may be affected) that they are unlikely to be detected in clinical trials that involve fewer people.
Monitoring also tells us about how the vaccine may affect people who have a greater risk of experiencing adverse events and who were less likely to be represented in clinical trials. This might include people who have underlying medical conditions or pregnant women.
As with all medicines there is a risk that some people will experience side effects, such as minor expected things like very mild inflammation at the site of an injection, to more serious adverse events like severe allergic reactions. Data about adverse events or adverse drug reactions are collected and analysed.
It is expected that the number of reported adverse events increases once a vaccine is used in the general population, simply because it is being used in more people. Pharmacovigilance collects data about all these events to understand what reactions and side effects are occurring so that assessments of the risks and benefits of a medicine can be reviewed.
It is also a way to provide healthcare professionals and the public with more information about how to use vaccines safely. The safety monitoring process also collects information about the impacts of any action taken.
Where does vaccine safety data come from?
Information about vaccine safety comes from several sources:
- Information published in scientific studies.
- Vaccine manufacturers.
- Databases that collect information about disease and causes of deaths.
- Systems that collect reports of adverse drug reactions. In the UK this is called the Yellow Card Scheme.
- International regulatory agencies.
In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for regulating medicines and medical devices, and safety monitoring. The MHRA is an executive agency of the Department of Health and Social Care.
When the MHRA approves a vaccine it also issues guidance for health professionals on its use. This includes details of extra measures that need to be put in place to protect patient safety. Once a vaccine is rolled out the MHRA continues to collect data from all the sources listed above.
Leaflets that must be provided with medicines also detail lists of side effects or adverse events that have been reported. While some of these are effects that are clearly linked to the vaccine or the vaccination process, others are not.
When testing or routinely using a vaccine, reports of any reactions are collected, even though they might not be directly linked to the vaccine. It is likely that some people in a large population will develop an unrelated coincident medical problem around the time of vaccination.
The Yellow Card Scheme
The Yellow Card Scheme collects and monitors information on safety concerns about medicines, medical devices and e-cigarettes. This includes all adverse events as well as concerns related to product quality or counterfeit products.
It relies on voluntary reporting by health professionals and patients when events occur. There is a dedicated page for COVID-19 vaccines and treatments with an online reporting tool. Adverse events can also be reported using the Yellow Card App. The system acts as a real-time early warning system, as reports will highlight areas of concern that require investigation.
Yellow card reports are then combined with information from other data sources so that medicine safety experts can assess the risks and benefits for each product. Having databases like this, and other data resources that can be linked, are important research tools. For vaccine safety monitoring, data from electronic health records are a particularly valuable research resource.
As more countries roll out COVID-19 immunisation programmes, more data about overall safety and any adverse events will accumulate.
What do we know about the adverse events related to vaccines?
Vaccines confer protection by stimulating an immune response to an antigen (a protein found on the surface of a virus or bacterium). The body recognises the antigen as foreign and this stimulates an immune response.
Side effects can include predictable, mild and short-lived reactions such as local swelling at the injection site, a fever or a headache. Adverse events are less predictable and can be more serious. For example, very rare events include neurological symptoms such as seizures or severe allergic reactions called anaphylaxis.
The frequency of adverse events in people are expressed as a ratio:
Very common: more than 1 in 10 people (≥1/10)
Common: more than 1 in 100 people (≤1/100 to <1/10)
Uncommon: more than 1 in 1000 people (≥1/1,000 to <1/100)
Rare: 1 in 10,000 people (≥1/10,000 to <1/1,000)
Very rare: fewer than 1 in 10,000 (< 1/10,000)
Not known: cannot be estimated from the available data.
A common side effect like redness and swelling at the injection site might occur in more than 1 in every 10 people, whereas a rare event like anaphylaxis might appear in 1 in every 900,000 people.
Adverse events can occur for different reasons and these can be grouped into four categories:
- Caused by the vaccine itself such as being allergic to the vaccine or one of the components in the formulation.
- Caused by the processes related to the delivery of the vaccine programme. Examples include incorrect vaccination preparation, giving the wrong dose, incorrect vaccine storage, or using an inappropriate technique for the immunisation. One example is fainting in response to the vaccination process; although not a side effect of the vaccine it is still recorded as an adverse event.
- Coincidental, an unrelated event would have happened anyway but because it co-occurred with immunisation it is still reported.
- Unknown, instances where there isn’t enough information to determine which of the previous categories were relevant.
It is considered essential to record any event so that any warning signs that a vaccine may cause harm can be quickly detected and acted upon. Scientific research using specialised data analysis methods are used to work out which events are linked to the vaccine or vaccination and which ones are unrelated coincidences.
What happens when an adverse event is identified?
This will vary according to the type of adverse event that is being reported. It may lead to changes in the patient information leaflet about possible side effects. It may require issuing advice to immunisers about vaccine handling and immunisation protocols. In some cases, the advice about who should receive a vaccine may change, based on an analysis of the risks and benefits. New research studies to explore adverse events might be needed to answer specific question about why a reaction occurs.
What do we know about the adverse events and COVID vaccines?
There are over 200 vaccines for COVID-19 at different stages of development. The first data about adverse events come from the clinical testing carried out in people in the research stages. This is supplemented by more data as vaccines are approved and used in the wider population.
So far, one vaccine has been approved for use in the UK, the Pfizer/BioNTech COVID-19 vaccine (the official product name is COVID-19 mRNA Vaccine BNT162b). The vaccine is approved for use in those aged over 16 years. The side effects and the frequency with which they occur have been published by the MHRA. Most are mild and resolve a few days after vaccination. Not everyone will be affected. They are:
may affect more than 1 in 10 people
may affect up to 1 in 10 people
may affect up to 1 in 100 people
|Pain at injection site||Injection site swelling||Enlarged lymph nodes|
|Fatigue||Redness at injection site||Feeling unwell|
The clinical studies of this vaccine reported data on adverse events. The incidence of serious adverse events was low and similar in the vaccine and placebo groups. The clinical trials also recorded how many participants died. There were four deaths in the placebo group and two deaths in the vaccine group. No deaths were linked to the vaccine.
Immunisations with the Pfizer/BioNTech COVID-19 vaccine began on 8 December. On the first day of the UK programme there were three reports of allergic reactions which may be linked to the vaccine. Two reports were of possible anaphylaxis and one was a report of a possible allergic reaction.
The people affected were treated promptly and recovered. Data from the clinical trials reported a very small number of people experiencing allergic reactions: 0.6% in the group that received the vaccine and 0.5% of people who received a placebo vaccine.
The MHRA reviewed and revised its advice on the use of vaccine the following day, 9 December. Anaphylaxis is a serious event because it can cause life threatening breathing and circulatory problems. In response the MHRA convened an expert review and subsequently issued further precautionary advice that anyone with a history of anaphylaxis to a medicine or food should not have the vaccine or receive a second dose of the vaccine.
Other advice on managing the risks, include a 15-minute monitoring period after the vaccine is given and resources to manage anaphylaxis (on site treatment resources and appropriately trained staff). Resuscitation facilities must be available in all locations where the vaccine is given.
This approach demonstrates a prompt, active and responsive vaccine safety monitoring policy. The research response to these adverse events is likely to be an exploration of the role of any underlying medical conditions and whether the events were linked to the vaccine or were coincidental. This will inform managing risk for future immunisations with this and other COVID-19 vaccines as they become available.
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