COVID-19 vaccines: studies for approval

The European Medicines Agency (EMA) needs many detailed studies to confirm that a vaccine is safe, provides adequate protection and is of suitable quality. As a public-health body safeguarding medicines in the European Union (EU), EMA only recommends approval of a vaccine for COVID-19 after a thorough evaluation demonstrating the same high standards of quality, safety and efficacy required for any other vaccine approved in the EU.

EMA published the information on this page for use during the COVID-19 public health emergency. EMA is no longer updating this page.

What types of studies are needed to approve a COVID-19 vaccine?

A company developing a COVID-19 vaccine must submit an application to EMA containing data from various studies:

• Pharmaceutical quality studies
• Non-clinical studies
• Clinical studies

Pharmaceutical quality studies

Pharmaceutical quality studies provide information about the vaccine’s quality. This includes:

• the vaccine’s active components, purity and other ingredients (e.g. stabilisers);
• the way the vaccine is manufactured and controlled;
• the vaccine's stability and shelf life;
• how best to store the vaccine.

A company developing a COVID-19 vaccine also needs to provide detailed information to justify the use of each ingredient in the vaccine, as well as the manufacturing technology it is using.

It can only produce the vaccine in approved, certified facilities. It needs to show that the vaccine's manufacturing will be consistent across those facilities.

It must also maintain agreed high standards for each batch of the vaccine that is released after it has been authorised.

As companies sometimes produce vaccines at a much larger scale than batches used in clinical trials, they must show that commercial batches of vaccines are of the required quality.

Non-clinical studies

Like all medicines, vaccines undergo non-clinical or laboratory studies before they are tested in humans.

These studies show whether the vaccine might cause safety problems, which could include effects on reproduction or development in extreme cases.

In addition, companies often carry out these types of non-clinical studies:

• Immunogenicity studies: these look at the types of immune responses a vaccine triggers. For example, they can look at the formation of antibodies or at long-term immune responses by 'memory cells' in the immune system;
• Animal-challenge studies: these look at whether animals given a COVID-19 vaccine are protected from disease when exposed to SARS-CoV-2, the virus that causes COVID-19;
• Biodistribution studies: some types of vaccine require these to show which tissues and organs in the body the vaccine is able to reach after injection, for how long and whether this has any toxic effect.

Clinical studies

Clinical studies are studies in humans that show how safe and efficacious a vaccine is.

For COVID-19 vaccines, these studies need to look at immune responses, efficacy and safety.

For adapted COVID-19 vaccines, EMA’s recommendations are based on all available evidence, including new data submitted for the adapted vaccines and an extensive body of existing evidence for the originally authorised COVID-19 vaccines. Clinical data for one adapted vaccine can help in the evaluation of other adapted vaccines.

National authorities and ethics committees in each country authorise and regulate clinical studies for COVID-19 vaccines. This safeguards the safety and rights of study participants. It also ensures that the data generated by the studies are robust.

Clinical studies with authorised or investigational medicines in the EU have to comply with good clinical practice (GCP). This covers international ethical and scientific quality standards for designing, recording and reporting studies in humans.

Compliance with these standards provides assurance that the rights, safety and wellbeing of study participants are protected, and that clinical-study data are credible.

If there are concerns over the conduct of a clinical study or the integrity of the clinical study data during the scientific evaluation of a vaccine, the CHMP will consider inspecting the study site and will request an inspection if necessary.

EMA works in close collaboration with international partners, sharing information on inspections and facilitating inspections when they are needed.

For more information, see: 

• Clinical trials in human medicines

For more information, see:

• Guidance for medicine developers and other stakeholders on COVID-19: Clinical trials for COVID-19 medicines
• Clinical trials in human medicines
• Good clinical practice

What are efficacy studies?

Efficacy studies are large studies that evaluate the benefit of a medicine. For vaccines, these studies usually involve thousands of volunteers. 

Developers first test the vaccine's efficacy in people who have not previously come into contact with the virus that causes COVID-19 - the so-called ‘naive populations’. People who have either come into contact with the virus or have been vaccinated present a certain level of immunity. This might need to be considered in the results if such individuals are included in efficacy studies.

The feasibility of determining whether a vaccine can protect people against COVID-19 depends on whether the virus is circulating and on whether there are any cases of disease that can be prevented.

How is the efficacy of COVID-19 vaccines studied?

In efficacy studies, volunteers randomly receive either the vaccine or an alternative. This alternative could be a vaccine that does not protect against COVID-19 or a placebo (a dummy treatment).

Normally, the doctors, clinical study participants and clinical trial personnel carrying out the study do not know who has received the vaccine and who has received the control. This is important to avoid biases when interpreting study results.

The studies measure efficacy ‘endpoints’ to see how well the vaccine works in the study and the level of protection it offers to participants.

Regulatory agencies recommend that the main endpoint (primary endpoint) should be how well a vaccine prevents laboratory-confirmed COVID-19 disease of any severity. This means how well the vaccine prevents symptomatic disease in people infected with SARS-CoV-2 as confirmed by a laboratory test.

Did you know..? Efficacy studies also look at other relevant 'secondary endpoints', which give an idea of the other benefits of the vaccine. For example, a vaccine may reduce: the number of people infected; the number of severe cases of a disease; the severity of the disease.

The reduction in the number of people needing hospitalisation or mechanical ventilation or the reduction in the number of deaths can help measure the efficacy of the vaccine in reducing disease severity.

As it becomes less feasible to conduct an efficacy study, for example because more and more people have already been exposed to COVID-19 or have been vaccinated against the virus, the immunogenicity of the vaccine (e.g. levels of antibodies or other types of immune responses induced by the vaccine) can be used instead as a surrogate for efficacy. This is also based on the knowledge accumulated on COVID-19 since 2020. 

EMA advises companies to discuss their development plans with the Agency in order to identify the most appropriate studies to support approval.

For the approval of variant-specific vaccines, companies need to demonstrate that they have better immune response against the variant than existing vaccines.

How many participants take part in efficacy studies and for how long?

For the initial approval of COVID-19 vaccines intended for a primary vaccination course, regulators usually require at least one main efficacy study in many thousands of participants. This enables regulators to reliably detect a sufficient number of cases of disease, which helps determine the level of protection that a vaccine can provide.

When efficacy is measured through immunogenicity studies, these generally involve fewer people than efficacy studies.

Initially, companies analyse the main study results after a few months of follow-up and submit the results to regulators, including EMA. This allows regulators to approve vaccines as soon as possible after the results confirm that the vaccine’s benefits exceed any potential risk. Study participants continue to be followed for at least two years. 

Did you know..? The continuation of efficacy studies is meant to allow the company to collect information on long-term protection and safety. This means that the company will collect some of the follow-up data after approval, when the vaccine is being used widely. This is acceptable, because regulators will have concluded that the data initially assessed are sufficient to show the vaccine’s efficacy and safety. Observational studies will also collect data on the effectiveness of the vaccine in real life, allowing for the monitoring of its performance in a timely manner. This allows medicine developers and regulators to take actions if necessary.

For more information, see:

• COVID-19 vaccines: development, evaluation, approval and monitoring: Monitoring vaccine safety and use in real life

What is the level of efficacy that can be accepted for approval?

EMA has not set a minimum level of efficacy for approval. This is because it looks at the overall balance of safety and efficacy for each vaccine individually before concluding on whether or not it will approve the vaccine.

For example, a vaccine could have other advantages, such as:

• very few side effects;
• easy storage and delivery;
• good results in a specific age group or type of population that may respond less well to other types of vaccines.

Nevertheless, medicine developers have been asked to design studies to demonstrate a rate of efficacy of at least 50%.

For the approval of variant-specific vaccines, companies need to demonstrate that these adapted vaccines have better immune response against the variant than originally authorised vaccines.

What do the different efficacy levels mean?

In a study measuring how well a vaccine prevented people from becoming ill from COVID-19:

Efficacy	What it means
50%	that there were 50% fewer cases among people who received the vaccine compared with those who did not (i.e. the vaccine prevented 50% of cases)
90%	there were 90% fewer cases among people who received the vaccine compared with those who did not (i.e. the vaccine prevented 9 out of 10 cases)
100%	nobody who received the vaccine got the disease

What clinical data is needed to approve a variant-specific vaccine?

The Agency’s recommendations on the possible authorisation of adapted vaccines are taken based on all the evidence submitted.

To tackle rapidly emerging variants, EMA has approved adapted booster vaccines based on all available evidence. This includes quality as well as non-clinical and clinical data from previous evaluations of comparable subvariants and / or other variants of concern. This has enabled EMA to extrapolate the impact of changes in vaccine composition on the immune response.

Approving variant-specific vaccines should be coordinated globally, considering all emerging data. This should include data on the impact of a particular virus variant on the effectiveness of the approved vaccines. It should also include information on the variant’s transmissibility and on the severity of disease it causes.

EMA is working with developers to define suitable development programmes for variant vaccines, including the type of clinical trials they can carry out to provide adequate evidence to support the approval of the adapted vaccines in the EU.

The Agency had previously issued guidance outlining the requirements for manufacturers planning to modify their COVID-19 vaccines, including the data that they needed to provide.

However, as the situation with the Omicron subvariants is rapidly evolving, some aspects of this guidance may no longer apply. EMA advises developers to discuss their specific product development plans with the Agency.

For more information, see: 

• Adapted vaccine targeting BA.4 and BA.5 Omicron variants and original SARS-CoV-2 recommended for approval (12/09/2022)
• First adapted COVID-19 booster vaccines recommended for approval in the EU (01/09/2022)
• Global regulators discuss path towards regulatory alignment on response to Omicron variant (13/01/2022)
• Reflection paper on the regulatory requirements for vaccines intended to provide protection against variant strain(s) of SARS-CoV-2

Which benefits might not be known when a COVID-19 vaccine is initially approved?

When EMA first approves a vaccine, some benefits may still be uncertain. The benefits only become clearer after the vaccine is in use.

Over time, regulators get more information about:

• protection against severe disease and death;
• asymptomatic cases after vaccination, i.e the number of people who get infected with the virus but do not develop symptoms. This is important because these people can still spread the virus to others;
• whether the vaccine can reduce the spread of the virus in the community. Reducing transmission will depend on many factors, including how many people get vaccinated;
• the vaccine’s effectiveness in the real world, i.e. outside the controlled setting of clinical studies.

How is safety studied before approval?

Clinical trials have to show that the benefits in protecting people against COVID-19 are far greater than the risks and the potential risk of side effects.

Several thousand individuals receive the vaccine at the time of evaluation. This allows regulators to assess side effects that affect at least 1 in 1,000 vaccinated people.

Adapted vaccines are expected to be as safe as the originally authorised COVID-19 vaccines. This is because the modifications in the composition of adapted vaccines are minor and EMA has extensive safety data on the originally authorised vaccines.

Also, the safety profile of adapted vaccines, measured as local and systemic side effects, was not significantly changed compared to the originally authorised vaccines.

Did you know..? As most side effects occur within four to six weeks after receiving a vaccine, for the originally authorised vaccines safety data have to cover at least six weeks after completion of vaccination, for approval purposes. However, the studies will follow volunteers up for at least a year to see if there are any longer-term side effects. Side effects of a new vaccine that are so rare that affect less than 1 in 10,000 people can only be detected after collection of very large data sets. This is likely to be feasible only once large numbers of people have received the vaccine. A robust safety monitoring plan is in place in the EU to gather and evaluate any side effects that may arise during vaccination campaigns promptly.

For more information, see

• Safety of COVID-19 vaccines
• COVID-19 vaccines: development, evaluation, approval and monitoring: Monitoring vaccine safety and use in real life
• Pharmacovigilance: Overview
• Treatments and vaccines for COVID-19: post-authorisation

What data have to be provided for special populations and age groups?

Initially, vaccine studies focus on adults, including older adults, as well as people with underlying diseases that put them at particular risk of severe COVID-19. Some studies may also include adolescents from 16 years of age.

People above 65 years of age should represent at least a quarter of the total number of participants in studies. This group is at greatest risk of severe COVID-19.

Results from earlier safety and immunogenicity testing determine whether these people should be included in large clinical studies.

Studies should also include people from ethnic minorities.

Investigations into the use of COVID-19 vaccines in children are carried out once there is sufficient information from studies in adults and adolescents.

For more information, see 

• Paediatric investigation plans
• COVID-19 guidance: research and development

What studies are needed after approval?

Data from long-term clinical studies on safety and efficacy are important for a number of reasons. These data allow the assessment of how protection against COVID-19 evolves over time, such as if the level of antibodies in the blood might go down after some time.

Long-term data are also important to assess whether there is any risk of vaccine-associated enhanced disease (VAED). VAED is a condition that would occur when a vaccinated person subsequently infected with a virus develops a more severe disease than they would have had if they were not vaccinated.

This has been seen in animal models given vaccines against SARS or MERS (different types of coronaviruses causing severe disease) and never with humans given such SARS or MERS vaccines. VAED has not been seen with COVID-19 vaccines in any studies done so far.

Long-term clinical studies help monitor how effective vaccines are and how long they protect people against COVID-19. This can help determine whether booster doses are needed.

Protection against COVID-19 has been shown to decrease as a result of the spread of new variants that can better evade the immune protection.

Adapted vaccines against variants of concern of SARS-CoV-2 have started to be approved in the EU. Long-term safety studies are also being carried out.

For more information, see:

• Adapted COVID-19 vaccines
• COVID-19 vaccines: key facts
• COVID-19 vaccines: development, evaluation, approval and monitoring

Monitoring COVID-19 vaccines in the real world

Once originally authorised, as well as adapted COVID-19 vaccines are deployed in mass vaccination campaigns, EMA makes use of real-world data to monitor their safety:

• Monitoring of COVID-19 medicines

How are clinical studies carried out in other parts of the world?

Since the COVID-19 pandemic affects people worldwide, it is important for companies developing COVID-19 vaccines to generate robust evidence that meets the needs of regulators around the globe. This is why EMA and other medicines’ regulators have agreed key principles on how to carry out clinical trials for COVID-19 vaccines.

Companies applying for approval of a vaccine in the EU must ensure that clinical studies meet stringent EU requirements no matter where in the world they took place.

For more information, see:

• Obtaining an EU marketing authorisation, step-by-step
• Conditional marketing authorisation
• COVID-19 guidance: assessment and marketing authorisation
• International Coalition of Medicines Regulatory Authorities (ICMRA)