< Vaccines

How do you know if a vaccine is safe and protects against COVID-19 ?

Text updated on 2021-01-29


Pre-clinical and then clinical trials (phase 1, 2 and 3) are used to evaluate the dosage, tolerance, potential toxicity, adverse effects, and efficacy of a vaccine. Then, once the vaccine has been granted marketing authorization, a pharmacovigilance phase begins to monitor the tolerance and efficacy of the vaccine under real-life conditions of use.

A vaccine must go through several phases of development.

First ofall, pre-clinical (animal)testing is usually carried out on rodents and then on monkeys. This is an essential step to select the best candidates and avoid giving humans vaccines that are ineffective or that would cause too many inflammatory reactions. These trials can often give excellent results in animals, but not necessarily in humans.

Next, clinical trials are conducted in humans. In the case of COVID-19, tens of thousands of people have volunteered for these clinical trials to determine if the vaccine is safe and effective. These trials include people from diverse racial and ethnic backgrounds, of different sexes and ages, possibly with a variety of chronic health problems (co-morbidities). Clinical trials have four stages. 

Phase I is the phase that evaluates the ideal dose and can provide a first glimpse of the potential toxicity of the vaccine. It is carried out on a few dozen volunteers to ensure that the vaccine is safe and does not cause severe adverse effects. Several dosages are tested. In addition, the nature of the immune response stimulated by the vaccine (level of neutralizing antibodies) is carefully analyzed. 

The second clinical phase, or Phase II, is the phase that sometimes allows for refining the dosage, continuing to evaluate adverse events and, most importantly, having some idea of the vaccine's effectiveness in humans. It is carried out on a larger sample (several hundred to several thousand people) and makes it possible to verify that the vaccinated people produce the antibodies required to fight the disease. At this stage, the goal is not necessarily to measure the rate of protection provided by the vaccine, but it can be done. 

Phase III is used to evaluate the tolerance andefficacy of the vaccine. In the context of COVID-19, it is usually conducted on 20 to 50,000 volunteers in real-life conditions. Volunteers are distributed randomly: either in the group of those who will receive the vaccine, or in the "control" group of those who will receive a placebo (an injection not containing the vaccine). In order to avoid any bias, the volunteers and the therapists do not know what they are administering and therefore the patient does not know what he or she is receiving. This is the so-called "double-blind" procedure.

Then, each person is followed for several months to monitor their health. The duration of follow-up depends on the frequency of the disease: it was very short for COVID-19 because we were in a pandemic phase with a lot of viruses circulating in the population. The vaccine group is then compared to the placebo group to see if the vaccine has an effect against COVID-19. All negative reactions to the vaccine, but also to the placebo, which usually occur in the days following the injections, are investigated and recorded. Volunteers are also observed on a long-term basis to detect any other problems. These large-scale trials make it possible to detect certain rare adverse reactions (but some, appearing months or years after vaccination, are not detected in phase 3), and to define in which age groups or population groups the candidate vaccine is effective or not.

Finally, Phase IV trials, which follow the marketing authorization of the vaccine, are conducted after the vaccine is marketed to clarify its use in populations that were not included in Phase II and III trials. This is a pharmacovigilance phase, to monitor tolerance to the vaccine under real conditions of use. The aim is to check whether very rare but serious adverse events occur in a few of the millions of people vaccinated and to monitor adverse events that may occur over the longer term.

The results of the trials are reviewed by experts independent of the companies that manufacture the vaccine and by government agencies and health authorities in each country. 

COVID-19 vaccine trials started in 2020. These clinical trials mobilize more than 200,000 participants worldwide, a multitude of research teams and considerable resources, including in emerging countries such as India and Kazakhstan. According to the World Health Organization, more than 180 vaccines are currently being studied, but only a few have undergone clinical trials in non-human primates or humans.

Against COVID-19, at least six vaccines have been the subject of large phase III clinical trials (more than 10,000 participants): those of Pfizer/BioNTech, Moderna, AstraZeneca, Novavax, CureVac, Janssen/J&J, but also Chinese and Russian vaccines for which we have less data. Most of the ongoing Phase III studies are designed to achieve a protection rate of at least 50%, with prevention of mild to moderate forms of the disease as the primary efficacy endpoint. Mild to moderate forms are more frequent and earlier onset than severe forms, and thus provide a more rapid indication of vaccine efficacy than if severe forms had been analyzed. However, this approach raises questions in a context in which it is the severe forms that burden health care institutions. Only one of these Phase III trials (Janssen's Ad26.COV2.S vaccine) selected moderate to severe forms of COVID-19.


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Sources

The different stages of vaccine development.

https://www.infovac.ch/fr/faq/developpement-d-un-vaccin

The FDA's June 2020 recommendations on the development of a vaccine against COVID-19.

Development and Licensure of Vaccines to Prevent COVID-19 - Guidance for Industry, June 2020

The FDA's October 2020 recommendations on the development of a vaccine against COVID-19.

Preparatory documents for the meeting of the Vaccine Committee scheduled for October 22, 2020, at the FDA.

Article presenting the key points concerning the main vaccines developed against COVID-19.

Korsia-Meffre, S.(2020). Vaccines against COVID-19 an update on the ongoing Phase III trials. Vidal. Article published on October 8, 2020.

Update on vaccines published on September 23, 2020 in the journal Nature.

Krammer, F. (2020). SARS-CoV-2 vaccines in development. Nature, 586(7830), 516-527.

Further reading

What are the different types of COVID-19 vaccines?

Do the variants call into question the efficacy of the vaccines?