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There have been news reports of 2 NHS workers having allergic reactions in response to the Pfizer/BioNTech COVID-19 vaccine.
Statement from Pfizer UK:
“We have been advised by MHRA of two yellow card reports that may be associated with allergic reaction due to administration of the COVID-19 BNT162b2 vaccine.
“As a precautionary measure, the MHRA has issued temporary guidance to the NHS while it conducts an investigation in order to fully understand each case and its causes. Pfizer and BioNTech are supporting the MHRA in the investigation.
“In the pivotal phase 3 clinical trial, this vaccine was generally well tolerated with no serious safety concerns reported by the independent Data Monitoring Committee. The trial has enrolled over 44,000 participants to date, over 42,000 of whom have received a second vaccination.”
Third-party expert comments:
Comment on the difference between anaphylaxis and anaphylactoid reactions:
Comment added 15/12/2020: Professor Saad Shakir, Director of the Drug Safety Research Unit, Southampton, said:
Anaphylactoid reactions with Pfizer/BioNTech COVID-19 vaccine: pharmacovigilance perspective and public information needs
From a pharmacovigilance perspective, the signal detection and evaluation process was straightforward. Anaphylactoid reactions are designated medical events. This means that they are in the list of events which are known to occur in association with exposure to medicines and vaccines. An occurrence of even a single designated case after exposure to a new product merits action, there is no need to wait to see if more cases occur to establish a trend. The MHRA acted promptly. They issued precautionary advice and committed to issuing further advice following investigation. Below is the advice from the MHRA in its entirety:
“Advice to Healthcare Professionals
This precautionary advice is being issued following two case reports of anaphylactoid reactions associated with administration of Pfizer BioNtech COVID-19 vaccine.
New advice:
Background
There have been two cases of anaphylactoid reactions in individuals with a strong past history of allergic reactions both of whom carried an adrenaline auto injector. These individuals developed symptoms of anaphylactoid reaction shortly after receiving the vaccine. Both recovered after appropriate treatment. We are seeking further information and will issue further advice following investigation.”
Further advice on the vaccination of people with significant allergic reactions is urgently needed.
Apparently no allergic events were reported during the premarketing clinical trials with the Pfizer/BioNTech vaccine. This emphatically demonstrates the vital importance of post-authorisation pharmacovigilance and safety studies. The spontaneous reporting system (known as the Yellow Card System in the U.K.) was able to detect these events because they are designated medical events. Other more robust pharmacoepidemiological study methods will inevitably be needed to detect other types of adverse events with COVID-19 vaccines. These include active surveillance and the use of electronic health records databases (which exist in the UK). Also there is a need to undertake ad hoc explanatory studies for unexpected events which emerge during the post-marketing phase. For example, research is now needed to better understand the biological basis for allergic reactions with mRNA COVID-19 vaccines.
The definition of “history of significant allergic reaction” is difficult. It is reasonable to use a temporary description of someone who needs to carry an adrenalin injection e.g. Epipen. The concern is that more people will be deprived of the benefit of the vaccine if the definition of those who should not use the vaccine is widened to people history of lesser forms of allergy. However at this stage, with the current limited knowledge, a wider list of people with history of allergic conditions provides a better safeguarding measure than a narrow list of allergic events. The last thing needed is for people with any form of allergy, genuine or presumed to any substances, to decide not to receive the vaccine. No one should decide not be vaccinated because of history of allergic condition without seeking advice from a healthcare professional.
From a pharmacovigilance perspective, more intense monitoring, using a range of monitoring and study methods and near real time reporting, is key to ensuring that the impressively effective vaccines for COVID-19 continue to be used to benefit us all.
Prof Saad Shakir, Director of the Drug Safety Research Unit (DSRU) near Southampton, said:
“Anaphylaxis is an allergic response by the body to external substances such as food, medicines and vaccines. The manifestations of anaphylaxis include effects on the cardiovascular, respiratory, gastrointestinal systems and the skin by way of severe rash. The blood pressure can drop, and breathing can become difficult.
“Treatment is with injectable adrenalin and later with corticosteroids and other supporting measures. Anaphylaxis is well known to occur with some food substances such as peanuts. This is why people who get vaccinated are asked to stay in the place of vaccination for a while to be monitored because anaphylaxis occurs early.
“However, the events that appear to have occurred after the Pfizer vaccine in two people were anaphylactoid reactions, which are allergic reactions that share some of the characteristics of anaphylaxis but are less severe. Prompt treatment was given.
“Both anaphylaxis and anaphylactoid and other allergic reactions are more likely to occur in people who have previous history to allergies.
“The ‘summary of product characteristics’ for the Pfizer vaccine includes a statement saying that this vaccine should not be given to people with hypersensitivity to active substances. A list of active substances was included in the SmPC but this was not specific.
“It seems that the advice now has been upgraded so that people should not be vaccinated with this vaccine if they have a history of allergic reactions severe enough to require them to use an EpiPen (Adrenalin) to inject when they get a severe allergic reaction. This is the correct risk minimisation action.
“As with all medicines and vaccines, larger number of people are exposed to them after authorisation, this expansion will unearth adverse events which were not observed during trials. It is impressive how swift this response was to the reports of these two anaphylactoid reports. We now have a risk minimisation measure which will exclude people who have history severe allergic reactions from being vaccinated with this COVID-19 vaccine. It is reassuring that the decision was made and communicated so promptly.”
Comment on the difference between anaphylaxis and anaphylactoid reactions:
Dr Louisa James, Lecturer in Immunology, Queen Mary University of London, said:
“Anaphylaxis involves a type of antibody called IgE which recognises a specific allergen and triggers the release of chemicals from immune cells on exposure to that allergen. Anaphylactoid reactions trigger the same responses as anaphylaxis but do not involve IgE antibodies.”
Prof Graham Ogg, Interim Director of the Medical Research Council Human Immunology Unit, University of Oxford, said:
“It will be important to now understand the specific nature of the reactions and the background medical history of the individuals affected so that any risks of reactions can be more closely defined. Staff are always prepared for the possibility of reactions and as with all medications, will continue to submit reports of any further episodes. In the meantime, reasonable precautions have been advised by the MHRA.”
Dr Andrew Garrett, Executive Vice President of Scientific Operations, ICON, said:
“The large clinical trial used to support vaccine approval by the MHRA excluded those with a “History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (e.g. anaphylaxis) to any component of the study intervention(s)”.
“The resulting UK patient leaflet stated that the vaccine should not be given to individuals who are allergic to the active substance or any of the other listed ingredients. In this respect the patient information was similar to the clinical trial exclusion criterion, and the approved vaccine labelling will have reflected the data received and reviewed by the MHRA to date.
“As more data accumulate from both clinical trials and clinical practice then one naturally expects the safety profile to be updated and refined, as with any medicine. The MHRA has moved quickly today to strengthen their direction on the basis of two allergic reactions in individuals with a history of allergic reactions – that is, to exclude individuals with a significant history of allergic reactions moving forward.
“As the vaccine roll-out begins, it is a reminder that it is important to follow strictly the conditions of the product labelling. In this case it is understandable that individuals will have little knowledge of their potential allergic susceptibility to the ingredients of a new vaccine but the precautionary principle should apply. Tuesday was a welcome cause for celebration, and there was an enthusiastic response from those vaccinated. Labelling may well expand in the future, but it would be wise to be cautious in these early days to avoid undermining public confidence – particularly given the vaccine is in limited supply. Careful questioning of those about to receive the vaccine is in order.”
Dr Charlie Weller, Head of Vaccines at Wellcome, said:
“Safety is the most important consideration for any vaccine trial. To ensure vaccines are safe and effective, independent regulators like the MHRA rigorously review the data before and during rollout to the wider population.
“It is encouraging that the MHRA are acting quickly and issuing clear guidance as soon as events occur. Any rare safety events will be reported and reviewed as this vaccine – and any other vaccine – is rolled out.
“Much more data would be needed to determine if there is any relationship between the vaccine and these reactions. Guidance would then be issued to those who might be at risk.
“As vaccine rollout is just beginning, many unanswered questions remain. Ongoing monitoring will help us to identify any consistent patterns of adverse events. As is normal for any vaccine, close and continued monitoring for safety and efficacy data as it is delivered will be essential.”
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at King’s College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
“The prescribing information for the vaccine issued by the MHRA includes a contraindication for use of the vaccine in any individual that is/has had an allergic reaction to the vaccine or to any of the components of the vaccine. It is understood that the people concerned had a history of allergy severe enough to require them to carry an adrenaline autoinjector; such people would be at increased risk of an allergic reaction to novel challenge compared to the population without a history of severe allergy. These two reactions were treated and it is understood that the people affected recovered well.
“Previous epidemiological studies of anaphylaxis suggests that an anaphylactic reaction might be observed within a community in up to 30/100,000 (approx 1/3300) people followed over a year, by chance alone (study from 2016). As these two events occurred in people with a history of severe allergy, it is sensible of the MHRA to draw attention to these reports and to suggest that individuals with a history of severe allergy not receive the vaccine at this time. MHRA is actively monitoring the safety of the vaccine during clinical use and can be expected to provide updates to practitioners as more information is gathered.
“The prompt reporting of these events using the yellow card scheme and the rapid issuing of additional information to guide practice shows that the safety monitoring system is working well.”
Prof Adam Finn, Professor of Paediatrics, University of Bristol, said:
“Severe allergic reactions to vaccines are unusual but staff administering vaccines are always trained and equipped to deal with them in the event they occur. The report of occurrence of two reactions as reported today will heighten awareness of this possibility among immunising teams and sensible precautions to avoid exposure of those who have had previous severe allergic reactions are being proposed while more experience of using this new vaccine accumulates.”
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“Allergic reaction occurs with quite a number of vaccines, and perhaps even more frequently with drugs. So it is not unexpected.
“The Pfizer data showed that about 0.6% of people had some form of allergic reaction in the trial on the vaccine, but about 0.5% on placebo. So there was a genuine excess of allergic reaction but this was small and the true rate is not known, and there is a lot of uncertainty around that estimate.
“The only thing that is contraindicated with this vaccine (meaning you mustn’t have it) is hypersensitivity to the vaccine or any of the excipients (other things in the vaccine), but some people won’t know if they have hypersensitivity to some constituents of the vaccine.
“What would be wise, as the MHRA have already advised, would be for anyone who has known severe allergic reaction such that they need to carry an EpiPen, to delay having a vaccination until the reason for the allergic reaction has been clarified.
“For the general population this does not mean that they would need to be anxious about receiving the vaccination. One has to remember that even things like marmite can cause unexpected severe allergic reactions.”
Prof Peter Openshaw, past-President of the British Society for Immunology and Professor of Experimental Medicine at Imperial College London, said:
“As with all food and medications, there is a very small chance of an allergic reaction to any vaccine. However, it is important that we put this risk in perspective. The occurrence of any allergic reaction was one of the factors monitored in the phase 3 clinical trial of this Pfizer/BioNTech COVID-19 vaccine, the detailed data from which was released yesterday1. In this, they reported a very small number of allergic reactions in both the vaccine and placebo groups (0.63% and 0.51%).
“Similar to the rollout of all new vaccines and medications, this new COVID-19 vaccine is being monitored closely by the Medicines and Healthcare products Regulatory Agency (MHRA). They will now investigate these cases in more detail to understand if the allergic reactions were linked to the vaccine or were incidental. The fact that we know so soon about these two allergic reactions and that the regulator has acted on this to issue precautionary advice shows that this monitoring system is working well.”
1 https://www.fda.gov/media/144245/download
All our previous output on this subject can be seen at this weblink:
www.sciencemediacentre.org/tag/covid-19
Declared interests
Prof Saad Shakir: “The Drug Safety Research Unit is an independent charity (No. 327206), which works in association with the University of Portsmouth. It receives unconditional donations from pharmaceutical companies. The companies have no control on the conduct or the publication of the studies conducted by the DSRU. Gilead is providing support for a methodological project led by the DSRU as a part of a large group of pharma companies, unrelated to this product.”
Prof Graham Ogg: “No COVID-19 conflicts of interest to declare.”
Dr Andrew Garrett: “I am employed by ICON which is a Contract Research Organisation. ICON provides pharmaceutical services to the pharmaceutical and biotechnology industries. ICON conducts clinical trials on behalf of Sponsors, including vaccine trials.”
Dr Charlie Weller: “No COI.”
Dr Penny Ward: “No COIs. I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections. Between December 2016 and July 2019 I served as Chief Medical Officer of Virion Biotherapeutics Ltd, a company developing antiviral treatments for respiratory viral diseases. Previous employee of Roche, makers of tocilizumab (anti IL6 antibody) and CMO of Novimmune, makers of empalumab (anti IFN gamma antibody).”
Prof Adam Finn: “No conflicts.”
Prof Stephen Evans: “No conflicts of interest. I am funded (one day per week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator on any grants obtained from them. I am the statistician to the ‘meta-Data Safety and Monitoring Board’ for CEPI. I am paid for my attendance at those meetings and will be paid expenses for travel if that occurs.”
Prof Peter Openshaw: “Peter Openshaw has acted as consultant, panel member or scientific advisor to GSK, Janssen (J&J) and Pfizer. These have not been specifically on COVID, but involve vaccine and antiviral compounds that might be effective against RSV or influenza.”
None others received.