The last month of 2020 has seen three COVID-19 vaccines approved for emergency use in various countries including the UK and USA. Current data from thousands of people who have been given these three vaccines have found that they are safe. At present, it is optional to get these vaccines in the UK and USA.
After a year which resulted in over 1.7 million deaths and multiple lockdowns, many people are welcoming the news that COVID-19 vaccines are starting to be given to the public. Widespread vaccination may mean that life can return to pre-pandemic normality, however this scenario depends on people’s willingness to get the jab. Some people are concerned about the safety of vaccines in general, whilst others are suspicious of the novelty and rapid turn-around time of COVID vaccines in particular. We asked 13 experts in immunology, biostatistics and vaccinology whether the COVID-19 vaccines are safe, here is what we found…
Which COVID-19 vaccines have been approved and what does that mean?
Vaccines, along with all other medications, are not allowed to be used until a country ‘approves’ them. This approval process is carried out in each country or group of countries by an independent agency. In the USA this is done by the FDA (Food and Drug Administration), in the UK by the MHRA (Medicines and Healthcare products Regulatory Agency) and in the European Union the EMA (European Medicines Agency). In order for anything to be approved by these agencies, it has to show that it is 1) safe and 2) does what it is meant to do.
There are numerous COVID-19 vaccines currently undergoing research and development. Although some of these are already being used in Russia and China, only three vaccines are currently approved for use in the UK.
Two of these three vaccines are mRNA-vaccines. One is a joint effort from Pfizer and BioNTech called ‘BNT162b2’ and one is manufactured by Moderna and called ‘mRNA-1273’. Both of these vaccines have also been approved in the USA and Canada. BNT162b2 has additionally been approved in 9 countries worldwide and it is also authorised by the EMA. The final vaccine is an adenovirus vector vaccine developed by AstraZeneca and the Oxford Vaccine Group at Oxford University called AZD1222. As well as the UK, it has also been approved in a few other countries including India, Argentina and Mexico.
Screenshot of a table of approved vaccines from the Regulatory Affairs Professionals Society’s vaccine tracker website taken on the 08/01/2020, since then the Moderna vaccine has also been approved in the UK.
How does a vaccine get approved?
In order for the COVID-19 vaccines to be approved by the agencies mentioned above, they must have proved themselves safe. The safety data that is scrutinised during the approval process covers every step of the vaccine’s journey, from the initial experiments in the lab to the manufacturing process. An important part of this data is the clinical trials. All drugs, including vaccines, pass through three clinical trial stages. These stages are more formally known as ‘phases’:
- Phase I ~ test the vaccine on a small group of volunteers (20-80) to check its safe and find the right dose
- Phase II ~ find out if the vaccine actually works by dividing 100-300 volunteers into two groups and giving one group the vaccine and the other group a placebo.
- Phase III ~ divide thousands of volunteers into a vaccine group and a placebo group randomly. Don’t tell the volunteers or the doctors who is in which group (this is called making the trial ‘double-blind’) and check if the vaccine is working and if there are any side effects.
If a trial is not successful, for example the results show that the vaccine is not actually preventing the disease or it is causing adverse side effects, the trial is stopped, and the vaccine is not approved.
Even once the vaccine has been approved, it then passes onto Phase IV, where it continues to be monitored and information is collected on adverse effects. This is important to establish whether there are very rare effects. For example, two people in the UK had an allergic reaction to the Pfizer vaccine after it was given to thousands . This sometimes happens in response to flu vaccines as well, and healthcare workers are ready to handle such reactions when they give the jab. Both people have fully recovered, but collecting information on this is useful, for example the UK has now issued precautionary advice to people who have severe allergies.
Dr Finn from the University of Pittsburgh explains that “All new vaccines continue to be monitored once they begin to be widely distributed. We are now well connected with the whole world so a single problem with the vaccine anywhere in the world will prompt quick examination and changes if warranted.”
What safety data is there?
All three COVID-19 vaccines have undergone all three clinical trial phases and no serious side effects were found.
Pfizer vaccine
For the Pfizer vaccine, 195 people were recruited in the USA-based Phase I trial and 456 were included in the Germany-based Phase II trial. In both trials, nobody who received the vaccine had any serious side effects. Pfizer’s Phase III trial has been published in a peer-reviewed journal and included over 40,000 volunteers in 152 sites worldwide. In this trial, volunteers were divided into two groups. One group was given two placebo (saline water) jabs 21 days apart, and one group the actual vaccine jabs. This means that in the end 18,366 people received the full 2 doses of the vaccine. For 14 weeks after the second jab all 18,366 volunteers were assessed for side effects, both by surveys and taking blood samples. After the second jab, only 0.8% of them got a fever. More common symptoms were soreness at the injection site and sometimes sore muscles and headaches. Professor Kennedy from the Mayo Clinic explains that “the vast majority of the side effects seen were expected and are a direct result of the immune response to the vaccine. Side effects are similar to what has been seen with most other licensed vaccines and ore occurring at similar rates and with similar levels of severity (mostly mild and moderate).” No one in the study had a severe reaction to the vaccine.
An important factor is that this Phase III study included people from diverse backgrounds: 49% were female and 37% were black, African-American or Hispanic. On top of this, the study included people who may be at a higher risk level: 35% of participants were obese, 21% had at least one coexisting condition and the median age of the volunteers was 52.
Moderna vaccine
The Moderna vaccine similarly included 120 people in their Phase I trial and 600 people in their Phase II trial. The results of the Phase III trial have been published in a peer-reviewed journal in which over 30,000 volunteers were divided into the placebo and vaccine groups. This means over 15,000 received the vaccine across 99 sites in the USA, and among these the recorded side effects of the vaccines were some pain at the injection site and more rarely fatigue and headaches. Comparing the outcome of volunteers in the placebo and vaccine groups found that there were no other symptoms that were more common in the people who received the vaccine than the other volunteers. Moderna’s trial also included a varied demographic. The mean age of volunteers was 51 years old, 10% were Black or African American and 20% were Hispanic or Latino.
Astrazeneca/Oxford vaccine
Over 1000 people were recruited to AstraZeneca’s Phase I and II trials. 40,000 people have been recruited for the Phase III trial, and interim results of the outcome of 5,000 people in sites in the UK, Brazil and South Africa have been published in a peer-reviewed journal. Like the Moderna and Pfizer vaccine, side effects included pain at site of injection and headaches or fatigue. From the published results, 12% of the volunteers were aged 56 or older and 67% of the participants in the Brazil site (which included 2063 people who received the vaccine) were white.
All of the above information is freely available for anyone to read (you can click the links to find the sources). On top of this, the regulatory agencies that approved these two vaccines had access to additional data that covers not only the clinical trials but lab and animal studies. This information is often more than 10,000 pages long and is carefully examined by the FDA, MHRA and EMA. On the UK government website you can read a summary of the public assessment report as well as additional information for each of the three vaccines (Pfizer, Moderna, AstraZeneca) that have been approved.
What is in the COVID vaccines?
All vaccines work by tricking your immune system to thinking it has been infected with a particular virus without actually causing the disease. The effect of this is that your body’s natural defence system is ‘trained’ to fight against the real threat. In order to trick the immune system, a vaccine needs to expose immune cells to something that looks a lot like the disease. Traditionally, this is achieved by using dead or modified versions of the virus or using just one bit of the virus (often a protein on the outside of the virus that the immune cells recognise).
Next-generation vaccines make use of genetic information in the form of DNA or RNA. The SARS-CoV-2 itself uses RNA as its genetic information. The RNA codes for all the virus’ machinery. Like all viruses, when SARS-Cov-2 infects cells its genetic information is used as a template to make more virus particles.
All three approved vaccines are next-generation vaccines, so they all make use of genetic information which codes for a part of the SARS-CoV-2 virus to mimic infection.
Moderna and Pfizer vaccines
Both Moderna and Pfizer’s vaccines are RNA vaccines. In order to trick the immune cells into thinking they have been infected without actually infecting them, these vaccines use a small section of the genetic material called RNA. This section of RNA only codes for the spike protein of the SARS-CoV-2 virus, which is the protein cells would normally recognise if they were infected. This means it is not possible to make the full SARS-CoV-2 from just this RNA. As Professor Crotty from the La Jolle Institute for immunology explains “the RNA message is for 1 single coronavirus protein. It takes 25 different coronavirus proteins to make a coronavirus, so there is no worry about the RNA making a virus.” RNA in itself is not harmful, in fact your cells make and use RNA all the time. “At any moment a human cell has 5000+ different RNA messages, and they are all temporary messages, like post-it notes that get torn up by the cells within minutes or hours after being read.” The RNA of these vaccines is packaged in tiny balls of fats called lipid nanoparticles. These lipids are broken down and eliminated by your cells, and the RNA from the vaccine is broken down within a day of injection. The other ingredients are water and some salts and sugars to keep these particles stable.
This technology of delivering RNAs by lipid nanoparticles has not been used for vaccines before. However, medicines that use lipid nanoparticles (called ‘nanomedicines’) have been in use since the 1990s, and to date over 20 different ones have been approved by the FDA or EMA. Some of these medicines are RNA-based, similar to the RNA vaccines. They are usually used for cancer and gene therapies.
Astrazeneca/Oxford vaccine
The Astrazeneca vaccine is not an RNA-vaccine. Instead, it uses a ‘viral vector’ to deliver genetic material to cells. The viral vector is a modified version of a harmless chimpanzee virus called an adenovirus. These viruses are non-replicating, which means they are cleared rapidly from your body, and they don’t make new viruses once inside cells. Adenoviruses, unlike SARS-Cov-2, use DNA as their genetic material instead of RNA. Therefore, for this vaccine to work, the genetic information from the SARS-CoV-2 virus which codes for the spike protein is translated into DNA and put inside the adenovirus particles. Despite the ‘language’ of the genetic material being different, it is still used in the same way and makes the spike protein which causes an immune reaction. Again, the other ingredients are there to keep these virus vectors stable and include things like water and salts.
The technology of viral vectors is well established, and research using viral vectors as vaccines has been carried out since the 1980s with several pre-clinical and clinical studies. Viral vector vaccines have been licensed, for example to protect against Ebola. Similarly to RNA-vaccines, this technology has also been investigated for use in gene therapies. However, so far no adenovirus viral vector vaccines have been licensed.
How come the vaccines were made so quickly?
Usually, vaccines take years to be developed and produced. The COVID-19 vaccines took less than one year. This is due to a number of reasons, three of which are explained by Dr Carnahan from the Vanderbilt University Medical Centre:
“One, all of the vaccines … were manufactured "at risk". This means that they were being produced before the clinical trials were even completed. This would never happen in a normal situation. Many of these costs were supported by various government organizations around the globe. Therefore, as soon as emergency approval was secured, distribution could begin.
Second, vaccine developers were rapidly analysing data as it emerged and communicating this in real-time to various regulatory agencies. There are often gaps of months to years between the various phases of clinical trials due to these activities alone.
Third, recruitment to clinical trials is often a slow and laborious process. There have to be people "at-risk" for the disease in many different demographic and health categories. Due to the immense scope of the pandemic, finding sufficient and appropriate volunteers was rapid.”
Importantly, the speed did not affect the clinical trials and safety aspects of the process: “The size, thoroughness, and complexity of the clinical trials conducted for the current COVID-19 vaccines were no different than traditional clinical trials. These are as safe as vaccines and interventions developed on much slower timelines.” – Dr Carnahan.
A balance of risk
Nothing in medicine is 100% safe – you don’t take medication for a disease you don’t have or a vaccine against a disease that doesn’t exist. Dr Hausdorff from PATH, a global not-for-profit public health organisation, explains that “all discussions of "safety" for vaccines (or medicines in general) have to start with discussions of how serious and frequent is the condition you are trying to prevent or treat. If the condition is very minor, then even trivial side effects may be not worth it. If the condition is very serious, then people will accept much bigger potential side effects”. Every medical intervention is a balance of risk vs benefit. In order for all three vaccines to be approved they have not only shown that they are safe but that they effectively protect against COVID-19. This protection from a virus which has so far caused over 1.7 million deaths globally is also an important consideration when thinking about vaccine safety.
Takeaway:
All 13 experts agreed with the scientific consensus that the COVID vaccines that have been approved by the proper regulatory agencies such as the FDA or MHRA are as safe as any other vaccine or medication. Nothing in medicine is risk-free and the decision to take a vaccine is entirely personal and dependent on a person’s individual circumstances.
Quotes in this article are from scientists answering the question 'Are the COVID-19 vaccines safe?' on the fact checking website metafact. An earlier version of this article is published on metafact and on sciencealert.
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