(Joint Statement from the International Coalition of Medicines Regulatory Authorities and World Health Organization)
Commonly reported adverse events
The most commonly-reported events with COVID-19 vaccines are expected vaccine side effects, such as headache, fatigue, muscle and joint pain, fever and chills and pain at the site of injection. The occurrence of these adverse events is consistent with what is already known about the vaccines from clinical trials.
Adverse events of special interest
Regulators approve and maintain an approval of a vaccine only if they determine that the known and potential benefits of the vaccine outweigh its known and potential risks.
Anaphylaxis is a very rare side effect that may occur with any vaccine. There have been some other reported adverse events which include facial weakness, seizures, loss of sense of taste or small and cardiac events, but none are confirmed to be causally related to the vaccines.
mRNA vaccines
The major adverse event of special interest reported for these vaccines, which include the Pfizer and Moderna vaccines is anaphylaxis. Regulators carefully review the reports of possible anaphylaxis to determine whether they are consistent with true anaphylaxis and whether they may have been caused by the vaccine. Anaphylaxis reports remains very rare (in the order of 10 cases per million vaccinated).
Guidance on the management of possible anaphylaxis is included in the Product Information/Label for these vaccines. Routine vaccination procedures include keeping people under observation for at least 15 minutes after vaccination and having appropriate medical treatment on hand so that anaphylaxis can be rapidly managed. These vaccines should not be given to people with a known history of a severe allergic reaction to any of the vaccine components. A second dose of mRNA vaccine should not be given to those who have experienced anaphylaxis to the first dose.
There have been some other reported adverse events, which include unusual bleeding and blood clotting disorders, facial weakness, seizures, loss of sense of taste or smell and cardiac events. Regulators monitor and carefully review if there is a causal relationship between the vaccines with those adverse events, and, if appropriate, they will be included in Product Information / Product Label of vaccines of concern.
Adenovirus vector vaccines
These include the AstraZeneca, Janssen, Gamaleya and CanSino Biologics vaccines. Internationally, the AstraZeneca and Janssen COVID-19 vaccines have been associated with a very rare and unusual clotting syndrome involving thromboembolic events (blood clots) with thrombocytopenia (low blood platelet count). This condition has been termed Thrombosis with Thrombocytopenia Syndrome (TTS). Medicines regulators are meeting regularly to share information about cases to better characterise this risk and understand this syndrome. Less information is available internationally about adverse events following the Gamaleya and CanSino Biologics vaccines.
The overall number of reports received of blood clots in the veins or arteries (including venous thrombosis or venous thromboembolism) occurring without thrombocytopenia is no higher than the expected background population rate for the more common type of blood clots in most countries.
The spontaneous reporting rates of thromboembolic events with thrombocytopenia vary by country and the precise incidences are difficult to estimate, but for the AstraZeneca vaccine, based on substantial use in Europe and the UK, the frequency of such events is very rare. Available estimates are of the order of 10-15 per million people vaccinated (note that for some countries this statistic is based on the numbers of reports of suspected cases of TTS rather than numbers of confirmed cases). Thromboembolic events with thrombocytopenia have also been reported in the United States for the Janssen vaccine, at a rate of about 2-3 per million doses administered. National regulators are continuing to monitor the issue closely and to publish up to date information on the numbers of cases reported and the latest estimates of the incidence.
The cases of thromboembolic events with thrombocytopenia after vaccination were mainly reported for younger rather than older individuals. This, together with the risk of serious illness or death associated with COVID-19 being much higher in middle-aged and older people, has led public health authorities in some countries to recommend that vaccination with the Astra Zeneca vaccine not be initiated in younger individuals.
Healthcare professionals should be alert to the signs and symptoms of thromboembolism and thrombocytopenia as well as coagulopathies after vaccination as TTS requires specific management. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms such as a severe or persistent headache, blurred vision, shortness of breath, chest pain, leg swelling, persistent abdominal pain or unusual skin bruising and/or petechiae (tiny purple, red, or brown spots on the skin) mostly occurring within around 4-20 days after vaccination, although some cases have been reported later than 20 days post vaccination. This information is in the Product Information / Product Label of the vaccines as approved by regulators.
Questions and Answers on COVID-19 vaccines
Q: How have the vaccines been developed so quickly? Does this mean that their safety and efficacy has been compromised?
A: The speed of development of COVID-19 vaccines has been unprecedented for several reasons, but the safety and efficacy requirements for vaccines have not been compromised, Vaccine development was facilitated by:
The massive financial investment by governments, industry and philanthropic organisations in vaccine development and the re-direction of much of the global research and commercial infrastructure for the development and manufacture of vaccines. Governments also enabled companies to take the commercial risk of manufacturing some vaccine stocks ahead of regulatory approvals.
New technologies adapted from the development of other vaccines – mRNA vaccines were developed for COVID-19 very rapidly after the sequence of the COVID-19 virus was determined, but the underlying technology had been under development since much longer and production could be scaled up very quickly. The adenovirus technology used for adenovirus vector vaccines was first tested with SARS, MERS and Ebola virus over the last 20 years, and so was able to be adapted quickly to COVID-19, which has several similarities to these viruses.
Clinical trial successes – it has been possible to rapidly recruit large numbers of volunteers into clinical trials and, with unfortunately high rates of infection in several countries, to complete trials with 10,000-50,000 people in a short period of time. Under normal circumstances, it may take many months or even a few years to carry out trials of this size to determine whether a vaccine is effective.
Very close collaboration – between regulators, industry and clinical researchers enabled clear indications of regulatory requirements and early access to results.
Intensive and insightful research – researchers predicted that the “spike protein” on the virus would be a good target for vaccine development, and almost all vaccines have been designed to induce a response to this protein. So far, the spike protein has produced a strong immune response in those vaccinated, and for those vaccines that have reported clinical results are highly protective from COVID-19 disease.
Q: Will mRNA vaccines affect the DNA of vaccine recipients?
A: No. The mRNA in the vaccine has not been shown to incorporate itself into the genes of vaccine recipients and breaks down in the weeks after vaccination. mRNA vaccines contain genetic instructions for our cells, which only read them and provide copies of the SARS-CoV2 spike protein. This enables the body’s natural immune systems to cause a response in vaccine recipients if they are later exposed to the virus.
Q: How long will COVID-19 vaccination provide protection for immunised people?
A: We do not yet know how long protection from any of these vaccines lasts. We will get better insights over the next 12 months.
The duration of protection provided by vaccines can vary. For example, the seasonal influenza vaccine is given annually, because the influenza virus mutates, and protection wanes over a number of months. Other vaccines, such as those for rubella or measles provide multi-year or even life-long protection from disease. Mutations in key viral proteins can mean that virus variants emerge. The SARS-CoV-2-coronavirus is prone to mutations that creates variants, some of which have become established in a number of regions of the world. The scientific community and regulators are very actively monitoring whether the current vaccines can continue protecting people from infection with new variants.
A number of vaccine developers are currently developing vaccines against the range of variants, and it is likely that booster shots with these vaccines will increase protection against known variants. Regulators have agreed that review of data on vaccines against variants will be facilitated based on assessment of immune response to the variant, in the same way that new seasonal influenza vaccines are evaluated each year.
Q: Why are there so many vaccine candidates?
A: As the global seriousness of the pandemic became rapidly apparent, development of effective vaccines for COVID-19 became the top priority of many pharmaceutical companies and medical research institutes. There was also unprecedented government and private sector investment in vaccine development. There is now a wide range of technologies for developing new vaccines – and many of the organisations developing COVID-19 vaccines have particular experience in one or more of these technologies. This has ensured that there would still be vaccines available if some were not approved for reasons of efficacy, safety or manufacturing challenges.
Q: What if many people start getting a reaction from a particular COVID-19 vaccine?
A: Short-term reactions, such as soreness at the injection site, fatigue or headache are common following any vaccination with COVID-19 vaccines. These reactions usually pass in a day or two. If new evidence becomes available that suggests that a specific serious adverse event may be linked to a particular COVID-19 vaccine then regulators will take action, working collaboratively on a global basis and liaise with public health authorities. The type of actions that can be taken depend on the nature of the adverse event, and could range from issuing safety warnings for patients, healthcare professionals and the community; updating the product information or consumer information for the vaccine to show contraindications for the use in particular patients (e.g. those with certain co-morbidities); to closely monitoring adverse events in certain groups of patients; preventing the release of a particular batch of vaccine through to temporary suspension of the use of the vaccine until more is known.
Q: How are regulators speeding up the time it takes to authorise a COVID-19 vaccine?
A: Many regulators globally have implemented faster access pathways for COVID-19 vaccines, without compromising on strict standards of safety, quality and efficacy.
Some countries have Emergency Use Authorisation pathways which assess the available data at the time of authorisation. Exercising these provisions is a matter for those countries, taking into account the benefits versus risks in the context of the prevailing domestic pandemic situation. Different countries may coin this pathway or authorisation routes differently but essentially, they follow the same principles.
Other countries have implemented accelerated/priority, conditional or provisional approval schemes.
Under normal circumstances, regulatory assessment begins once all information to support registration is available. For COVID-19 vaccines, many regulators have agreed to accept data on a rolling basis to enable early evaluation of data as it becomes available. Regulators will only be in a position to make a provisional approval decision for a vaccine once there is sufficient data to support adequately the safety, quality and effectiveness of the vaccine for its intended use. If a decision is made to grant provisional or conditional approval, it will be based on the requirement for the sponsor to submit more comprehensive, longer term clinical data, stability data and other information with agreed timelines.
Q: Did our country approve this COVID-19 vaccine, or are we relying on another country’s approval?
A: Most countries are carrying out independent regulatory evaluations on the submitted data for each vaccine. However, to ensure a more efficient use of resources and expertise, regulators in different countries are communicating closely on safety, efficacy and quality data and discussing technical issues as they may arise. In many cases principles of WHO Good Reliance Practices and collaborative mechanisms leverage the output of other regulators.
Q: Why weren’t very rare blood clots with low platelets with the AstraZeneca or Janssen vaccines picked up during clinical trials?
A: Thromboembolic events with concurrent thrombocytopenia are very rare – with estimates based on the number of spontaneous reports suggesting an overall incidence on the order of 10-15 cases per million doses. The clinical trials of these vaccines included large numbers of people, often with 10,000 to 20,000 individuals in the active vaccine arms, but even in trials of this size it was statistically unlikely that such very rare events would be detected. This shows the importance of continual safety monitoring during the use of these vaccines, to allow very rare events to be detected and investigated further.
