Potential Side Effects of COVID-19 Vaccines

--- title: Potential Side Effects of COVID-19 Vaccines tags: live-v0.1, facts, vaccines permalink: https://c19vax.scibeh.org/pages/sideeffects ---  {%hackmd 5iAEFZ5HRMGXP0SGHjFm-g %} {%hackmd GHtBRFZdTV-X1g8ex-NMQg %} # The potential side effects of COVID-19 vaccines [TOC] ## Efficacy vs. side effects Our [facts page about the COVID-19 vaccines](https://c19vax.scibeh.org/pages/c19vaxfacts) highlights the efficacy of the three main vaccines available to date (Pfixer-BioNTech, Moderna, and Oxford-AstraZeneca) and explains how those data were obtained. All trials involved the same basic design: participants were randomly assigned to a control (placebo) group or to the vaccination group. The [Pfizer-BioNtech trial](https://www.nejm.org/doi/full/10.1056/NEJMoa2034577?query=featured_home) involved 43,448 individuals; the [Moderna trial](https://www.nejm.org/doi/full/10.1056/NEJMoa2035389?query=featured_home) involved 30,420 participants; and the [Oxford-AstraZeneca](https://linkinghub.elsevier.com/retrieve/pii/S0140673620326611) trial recruited 23,848 participants of whom 11,636 were included in the interim analysis that has been published. Altogether more than 80,000 people were enrolled in those trials, and so there was considerable opportunity to observe side effects. A useful summary of the known side-effects of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines --- the two which are authorised for use in the UK as of 1st Jan 2021--- can be found in the [“Green Book”, which is a U.K. manual for healthcare workers who administer vaccines](https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948757/Greenbook_chapter_14a_v4.pdf): > Local reactions at the injection site are fairly common after Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2, primarily pain at the injection site, usually without redness and swelling. Systemic events reported were generally mild and short lived (Walsh et al, 2020). In the final safety analysis of over 21,000 participants 16 years and older, the most common events were injection site pain (>80%), fatigue (>60%), and headache (>50%). Myalgia, arthralgia and chills were also common with fever in 10-20%, mainly after the second dose. Most were classified as mild or moderate. Lymphadenopathy was reported in less than 1%. (Polack et al, 2020). Four cases of Bell's palsy were reported in vaccine recipients in the trial. Although within the expected background rate, this will be monitored closely post-implementation. Side effects were less common in those aged over 55 than those aged 16 to 55 years. Severe systemic effects, defined as those that interfere with daily activity, included fatigue in 4% and headache in 2%. There was no signal to suggest that prior vaccination led to enhanced disease with only 1 case of severe COVID-19 in the 8 vaccine failures. (Polack et al, 2020). > > From early phase trials, mild pain and tenderness at the injection site was common with AstraZeneca COVID- 19 vaccine occurring in 88% of 18-55 year olds, 73% of 56-69 year olds and 61% of people aged 70 years or over; similar levels were reported after each dose. Short lived systemic symptoms including fatigue and headache were also common but decreased with age, being reported in 86%, 77%, and 65% of those aged 18-55, 56-69 and 70 years or over respectively; most of these were classified as mild or moderate. These reactions were unusual after the second dose (Ramasamy et al, 2020). Mild fever (>38 ̊C) was recorded in the first 48 hours for around a quarter of younger participants and but was not reported in those over 55 years of age or in any age group after the second dose (Ramasamy et al, 2020). Fever can be modified by the prophylactic use of paracetamol, which does not affect the immune response to this vaccine (Folegatti et al, 2020). In the phase 3 study, injection site reactions, mild fever, headache, myalgia and arthralgia occurred in more than 10% of vaccinees. Less than 1% reported lymphadenopathy or an itchy rash. Only one serious adverse event was reported as possibly linked to the vaccine; this was a case of transverse myelitis which occurred 14 days after dose 2. There was no signal to suggest that prior vaccination led to enhanced disease. (Voysey et al, 2020). **In a nutshell, the main side effects are pain at the site of the injection, headache, fatigue, muscle aches, fever and chills. These problems usually resolve after 1-2 days.* ## Severe allergic reactions (“anaphylaxis”) If 1,000,000 people get vaccinated (using any existing vaccine), [one person](https://vaccine-safety-training.org/anaphylaxis.html) can be expected to have a severe allergic reaction known as anaphylaxis. People who develop severe allergic reactions normally make rapid and full recoveries and the healthcare professionals who give vaccines are trained and equipped to manage these rare events. Severe reactions tend to occur very rapidly after injection. The rates of severe allergic reactions following the Pfizer-BioNTech and Moderna mRNA vaccines are also very low, but may be higher than seen for other vaccines. A recent study by [Banerji et al. (2020)](https://dx.doi.org/10.1016/j.jaip.2020.12.047) reported 10 severe allergic reactions after more than 2,000,000 vaccinations with the Pfizer-BioNTech vaccine, equating to a rate of around 1 in 200,000. None of those events entailed any long-term effects or fatalities, and all patients were treated immediately with complete resolution of symptoms. To guard against those unlikely events, people who receive these vaccines are asked to remain under observation for a period after the injection so that medical staff are on hand to help if they have a reaction.  :::info To put this into context, about 5% of Americans (1 in 20) [have suffered anaphylaxis](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589409/) from a variety of causes, including exposure to certain foods (e.g., nuts, seafood) or insect bites. The risk of anaphylaxis from the COVID-19 vaccine (1 in 200,000) is therefore **10,000 times smaller** than our background risk. ::: ## What about long-term side effects? Long-term side-effects cannot be evaluated until the appropriate time has passed since a large number of people has been vaccinated. In the trials to date, people were monitored for more than 3 months after they received the first dose. However, given the known risk that COVID-19 can cause long-term damage (see our [facts page about COVID-19](https://c19vax.scibeh.org/pages/covidfacts)), the risk of long-term side effects from the vaccines is likely to be far smaller.  ## Risks of blood clots ("CVT" & "PVT") The occurrence of blood clots after vaccination is a very rare event; indeed, there is a higher risk from Covid-19 than from vaccination. The relative risk of a blood clot in the brain (known as CVT - central vein thrombosis) is about 6-10 times higher from Covid-19 than from an mRNA vaccine like Pfizer. For a blood clot in liver (known as PVT - portal vein thrombosis), the risk is 7-14 times higher from COVID than from the vaccine. ![](https://i.imgur.com/k6d9h01.png) **Relative risk of CVT and PVT after a diagnosis of COVID-19 compared to matched cohorts of people with a diagnosis of influenza (left) or receiving an mRNA vaccine (right). Horizontal lines and numbers in brackets represent the 95% confidence intervals. Since the confidence intervals do not include the value of 1, these results are statistically significant.** Source: [Cerebral venous thrombosis and portal vein thrombosis: a retrospective cohort study of 537,913 COVID-19 cases](https://osf.io/a9jdq/)). ## Latest updates (January 2021 onward) The European Medicines Agency [released its first safety update](https://www.ema.europa.eu/en/news/first-covid-19-vaccine-safety-update-published) about the Pfizer/BioNTech vaccine on 29 January 2021. > "It concludes that safety data collected on Comirnaty use in vaccination campaigns is consistent with the known safety profile of the vaccine, and no new side effects were identified." Two items from the [detailed report](https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-comirnaty-january-2021_en.pdf) are worth highlighting. * First, based on U.S. data, it reports the incidence of severe allergic reactions as being approximately 11 cases per million vaccinations. This is slightly higher than earlier estimates (see [above](https://hackmd.io/4OKKEkeBTb2WvIuOXOoiEg?both#Severe-allergic-reactions-%E2%80%9Canaphylaxis%E2%80%9D)), but is still small (around 1 in 100,000) and can be managed by healthcare professionals. * Second, the Agency reviewed a number of deaths following vaccinations that were reported in Norway and concluded that their "review did not suggest a safety concern." We have examined the issue of deaths following vaccinations [in detail on one of our Myths pages](https://hackmd.io/@scibehC19vax/misinfo_myths#FACT-Sadly-old-frail-and-vulnerable-people-sometimes-die). On April 12 2021, [the CDC and FDA chose to 'pause' the Johnson & Johnson/Janssen COVID-19 vaccine](https://www.cdc.gov/media/releases/2021/s0413-JJ-vaccine.html), after administering almost 7 million doses. This is to investigate 6 cases (including 1 death) of clots called CVST (cerebral venous sinus thrombosis) among women between the ages 18 and 48. Both the type and frequency of this clot are comparable to the AstraZeneca vaccine due to them both utilising the adenoviral vector method, as appose to the RNA method that is seen in the Pfizer and Moderna vaccines. We will report further updates from public health agencies as they become available. ## Blood clots and the Oxford AstraZeneca coronavirus vaccine Although several countries temporarily suspended the use of AstraZeneca's coronavirus vaccine as a precaution after a number of recipients suffered blood clots in the days and weeks following the vacciantion, the European Medical Agency (EMA) still states that [the benefits of the AstraZeneca vaccine still outweigh the risks](https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots). Around 20 million people in the UK and EEA had received the vaccine as of March 16, 2021 and EMA (European Medical Agency) had reviewed only 7 cases of blood clots in multiple blood vessels (disseminated intravascular coagulation, DIC) and 18 cases of CVST (Cerebral Venous Sinus Thrombosis). The reported cases were almost all in women under 55. EMA's safety committed [confirmed on 18 March 2021](https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots) that: * The benefits of the vaccine in combating the still widespread threat of COVID-19 (which itself results in clotting problems and may be fatal) continue to outweigh the risk of side effects; * The vaccine is not associated with an increase in the overall risk of blood clots (thromboembolic events) in those who receive it * However, the vaccine may be associated with very rare cases of blood clots associated with thrombocytopenia, i.e. low levels of blood platelets with or without bleeding, including rare cases of CVST. The WHO (World Health organisation) came to [similar conclusions and recommendations on 19 March 2021](https://www.who.int/news/item/19-03-2021-statement-of-the-who-global-advisory-committee-on-vaccine-safety-(gacvs)-covid-19-subcommittee-on-safety-signals-related-to-the-astrazeneca-covid-19-vaccine): * The AstraZeneca COVID-19 vaccine continues to have a positive benefit-risk profile, with tremendous potential to prevent infections and reduce deaths across the world. * The available data do not suggest any overall increase in clotting conditions such as deep venous thrombosis or pulmonary embolism following administration of COVID-19 vaccines. Reported rates of thromboembolic events after COVID-19 vaccines are in line with the expected number of diagnoses of these conditions. Both conditions occur naturally and are not uncommon. They also occur as a result of COVID-19. The observed rates have been fewer than expected for such events. Furthermore, [interim trial data from the USA, Chile, and Peru released on the 22 March 2021](https://www.ox.ac.uk/news/2021-03-22-results-usa-trial-oxford-vaccine?fbclid=IwAR04FHmna1ZBbKS2iCzyqb6WXu8G-fwPE1Frrt0nNNVJ7ozwnJ6UyXg8Hls) showed that the AstraZeneca vaccine efficacy was safe with no increased blood clot risk. Over 32,000 people took part in the study. ### Update following MHRA and EMA decisions on AstraZeneca’s COVID-19 vaccine (7th April 2021) The UK’s [Medicines and Healthcare products Regulatory Agency (MHRA)](https://www.gov.uk/government/news/mhra-issues-new-advice-concluding-a-possible-link-between-covid-19-vaccine-astrazeneca-and-extremely-rare-unlikely-to-occur-blood-clots) and [European Medicines Agency (EMA)](https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood) completed their assessment of extremely rare blood clotting events with low platelets from over 34 million people vaccinated with AstraZeneca’s COVID-19 vaccine in the UK and EU. Neither agency identified any risk factors, such as age or gender, or a definite cause for these extremely rare events. However, they came to the view that these events have a possible link to the vaccine and requested they be listed as an extremely rare potential side effect. Overall, both of these reviews reaffirmed that the vaccine offers a high-level of protection against all severities of COVID-19 and that these benefits continue to far outweigh any risks. EMA is due to provide further context on the risk of blood clots, with this report due to come out by 22/4/21 at the latest. In addition, the [World Health Organisation (WHO)](https://www.who.int/news/item/07-04-2021-interim-statement-of-the-covid-19-subcommittee-of-the-who-global-advisory-committee-on-vaccine-safety) said that, based on current information, a causal relationship is considered plausible but is not confirmed, adding that further specialised studies are needed to fully understand the potential relationship between vaccination and possible risk factors. Furthermore, the WHO noted that, whilst concerning, the events under assessment are very rare, with low numbers reported among the almost 200 million individuals who have received the AstraZeneca COVID-19 vaccine around the world. The MHRA has undertaken a thorough review into UK reports of a very rare and unlikely to occur 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. Up to and including 31 March 2021, the MHRA had received 79 UK reports of blood clotting cases alongside low levels of platelets following the use of the COVID-19 Vaccine AstraZeneca. Of these 79 cases: * 44 were of CVST with thrombocytopenia * 35 were of thrombosis in other major veins with thrombocytopenia * 51 were in women and 28 in men (age range from 18 to 79). It should be more women have been vaccinated with COVID-19 Vaccine AstraZeneca than men. * Sadly, of the 79 people suffering some form of thrombosis, 19 have died – 13 females and 6 males. * All cases occurred after a first dose of the vaccine. 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. ## Update on 3 June 2021 after more evidence To date and overall, [for every million doses of AstraZeneca vaccine given approximately 10 people develop blood clots and unusual bleeding](https://www.gov.uk/government/publications/covid-19-vaccination-and-blood-clotting/covid-19-vaccination-and-blood-clotting). This is seen more often in younger people and tends to occur between 4 days and 4 weeks following vaccination. Therefore, on the 7th May, the [Joint Committee for on Vaccination and Immunisation in the UK (JCVI) advised](https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/JJUpdate.html) that, in addition to those aged under 30, unvaccinated adults aged 30 to 39 years who are not in a clinical priority group at higher risk of severe COVID-19 disease, should be preferentially offered an alternative to the AstraZeneca vaccine; this should only be the case where no substantial delay or barrier to access to vaccination would arise. ## Blood clots and the Janssen COVID-19 Vaccine There is a plausible, causal relationship between the [Janssen Covid-19 Vaccine and rare and serious, adverse event—blood clots with low platelets](https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/JJUpdate.html) (thrombosis with thrombocytopenia syndrome, or TTS). * It occurs at a rate of about 7 per million vaccinated women between the ages of 81 and 49 years old. * For women 50 years and over, and men of all ages, this adverse event is rarer still. ## Country-specific links for clinicians/patients to report side effects * [Austria](https://www.basg.gv.at/marktbeobachtung/amtliche-nachrichten/detail/covid-19-nebenwirkungsmeldungen?sword_list%5B0%5D=covid&cHash=f43e4277d31e037dc5022af716d9c23f) * [Belgium](https://famhp-vons.prd.pub.vascloud.be/fr/form/PVH) * [Croatia](https://primaryreporting.who-umc.org/Reporting/Reporter?OrganizationID=HR) * [Cyprus](https://www.phs.moh.gov.cy/yellowcard/index.jsf) * [Czech Republic](https://www.sukl.eu/medicines/phv-4-version-7) * [Denmark](https://laegemiddelstyrelsen.dk/en/sideeffects/side-effects-of-medicines/report-a-side-effect/humans/Meld-en-bivirkning-ved-en-COVID-19-vaccine---borgere-e-blanket/) * [Estonia](https://www.ravimiamet.ee/en/pharmacovigilance) * [Finland](https://www.fimea.fi/web/en/for_public/safety_of_medicines/submitting-a-report-on-an-adverse-reaction) * [France](https://ansm.sante.fr/actualites/point-de-situation-sur-la-surveillance-des-vaccins-contre-la-covid-19-periode-du-26-03-2021-au-01-04-2021) * [Germany](https://nebenwirkungen.bund.de/nw/EN/home/home_node.html) * [Iceland](https://www.serlyfjaskra.is/Aukaverkun/Registration/RegistrationSteps.aspx) * [Ireland](https://www.hpra.ie/homepage/about-us/report-an-issue/covid-19-vaccine-adverse-reaction) * [Italy](https://www.aifa.gov.it/en/moduli-segnalazione-reazioni-avverse) * [Lithuania](https://www.vvkt.lt/index.php?3341007673) * [Malta](http://www.medicinesauthority.gov.mt/adrportal?l=1) * [Netherlands](https://english.cbg-meb.nl/topics/mah-reporting-adverse-events) * [Romania](https://www.anm.ro/medicamente-de-uz-uman/farmacovigilenta/raporteaza-o-reactie-adversa/) * [Sweden](https://www.lakemedelsverket.se/en/reporting-adverse-reactions-events-and-incidents/suspected-adverse-reactions-from-medicinal-products/adverse-events-in-humans) * [Spain](https://www.aemps.gob.es/la-aemps/ultima-informacion-de-la-aemps-acerca-del-covid%E2%80%9119/vacunas-contra-la-covid%E2%80%9119/farmacovigilancia-de-vacunas/?lang=en) * [Slovenia](https://www.jazmp.si/humana-zdravila/farmakovigilanca/porocanje-o-nezelenih-ucinkih-zdravil/) * [United Kingdom](https://coronavirus-yellowcard.mhra.gov.uk/) * [United States](https://vaers.hhs.gov/) ---- Page contributors: Stephan Lewandowsky, Adam Finn, Jolanta Bernatoniene, Akil N. Khalid, Laura Rivini, Mark Winfield {%hackmd GHtBRFZdTV-X1g8ex-NMQg %} {%hackmd TLvrFXK3QuCTATgnMJ2rng %} {%hackmd oTcI4lFnS12N2biKAaBP6w %}