We are all hoping for a vaccine that will protect us from COVID-19, as soon as possible. But each vaccine candidate must first be tested in humans in clinical trials before it can be given to the public. Let’s take a look at how scientists determine the efficacy and safety of a vaccine candidate and how they attempt to increase the pace of these studies, which usually take place over many years.
This week, British scientists announced that in January they would begin a first “challenge” -type clinical trial on healthy volunteers who will be deliberately infected with SARS-CoV-2. This experiment should speed up the development of a vaccine against COVID-19, they argued. First, they will seek to determine the minimum dose of virus that is necessary to cause active infection in healthy young people aged 18 to 30. Second, they will enroll new volunteers who will first receive a vaccine candidate, and who will then be exposed to the dose of virus required to induce COVID-19 to see if the vaccine will protect them from infection. This way of doing will make it possible to know if a candidate vaccine is effective in the space of ten weeks, while by the current method, it will take months and will require the vaccination of tens of thousands of people, underline the investigators. of Imperial College London.
It is true that “challenge” type clinical trials can greatly accelerate the process of evaluating the efficacy of a candidate vaccine and reduce the number of participants required for the study, confirms Benoît Mâsse, professor at the School of Public Health of the University of Montreal. But given the specific context of COVID-19, they raise important ethical issues, underline Françoise Baylis, professor and researcher at Dalhousie University, and Bryn Williams-Jones, bioethicist at the School of Public Health of the Montreal university. This is why vaccine manufacturers have so far not taken this type of approach.
According to the randomized controlled study protocol that is conventionally used to test vaccines, one half of the group of participants is given the candidate vaccine and the other half a placebo. Neither the investigators nor the participants know what each participant receives. Participants then go about their business and lead their normal lives, during which time they are at risk of encountering and becoming infected with the virus.
In such a type of study, the effectiveness of the vaccine is determined by comparing the number of cases of COVID-19 infections in the vaccinated group to that seen in the placebo group. If both groups have the same number of infections, the vaccine will not work. On the other hand, if there are much less infections among the vaccinated, it will mean that it is effective, but partially. “It is normal that there are infections among the vaccinated, because we do not expect the vaccine to be 100% effective,” says Dr.re Caroline Quach, immunologist and infectious disease specialist at CHU Sainte-Justine.
For the vaccine to be 100% effective, there should be no infection in the vaccine group. Health Canada and the Food and Drug Administration (FDA) have planned to approve only vaccine candidates with an efficacy of at least 50% on their territory, which would result in at least half the number of infections in the country. vaccinated group than in the placebo group. Such effectiveness “would be comparable to that of the vaccine against the seasonal flu, which varies between 40 and 60%”, notes the Dre Quach.
“If we observe an efficiency of 50%, this implies that statistically, we will have a confidence interval whose lower limit will be close to 30%”, specifies Benoît Mâsse, before adding that most of the clinical trials in progress want to exclude vaccines with less than 30% efficacy. “The lower bound of 30% is a cost-benefit argument. Below this value, vaccination campaigns will bring almost no benefit, while they will cost billions. But if you do a good vaccination campaign with a vaccine that is 50% effective, it will help deconfin, because the vaccine will halve the risk of infection, ”he says.
Number of infections
But back to the method used to determine the effectiveness of a vaccine candidate. The validity of a classic study depends primarily on the number of infections that will occur in the participants. The number of infections to reach is usually determined in advance in the study protocol.
Considering the fact that the participants are not intentionally infected as in a “challenge” type study and that they will contract COVID-19 by chance, it is understandable why it will take much longer before reaching the number of infections. required. It is also understandable why these classic studies require a large number of participants, in the order of 30,000 at least. “The number of participants that should be enrolled for a phase 3 study depends on the incidence of infection in the area where the vaccine is being tested,” says Mâsse.
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This is the reason why investigators choose to conduct these clinical trials in regions of the world with high infection rates. In some US states and countries in Europe, these rates are so high that people have a great chance of being exposed to the virus, so there is no real need to artificially infect them, says Dr.re Quach. “Certainly it will take longer than vaccinating and challenging [voulant dire infecter volontairement les participants], but it will also allow us to accumulate data on the safety of the vaccine over a longer period. “
Normally, regulatory agencies require positive results from two independent Phase 3 studies. But given the urgency, we do not have the luxury of carrying out two studies, so we will only do one, but which will be quite a bit larger, called a pivot study, and whose criteria will be negotiated with regulatory bodies, says Mâsse.
Interim analyzes of the data obtained to date in the 11 ongoing Phase 3 clinical trials are also planned in the near future. These analyzes, which are done before the full study is completed, are carried out by a committee made up of biostatisticians, who are adept at judging the level of uncertainty in the data, physicians, laboratory analysis specialists, experts in vaccinology, bioethicists and representatives of the countries where the studies are carried out. All must be “independent of the pharmaceutical company that produces the vaccine and of the team conducting the study,” said Mâsse, who chaired the committee responsible for conducting an interim analysis of the study of the Canadian vaccine against. Ebola that was taking place in Guinea. In principle, the report and recommendations that are made by this committee are sent only to the sponsor of the study funding it. They remain “secret, because we do not want the information they contain to influence the value of the company’s shares,” says Mâsse.
If this analysis indicates that “the results are quite positive and committee members are fairly certain that the vaccine under study is safe and has a minimum of 50% efficacy, the veil will be lifted on the data. and we will notify the FDA and Health Canada in order to obtain permission to start extended access studies that would allow vaccination outside of the protocol, that is to say without placebo, ”explains Mâsse.
If, on the other hand, the interim analysis shows that the evidence is not strong enough and that there is too much variability, it will be recommended to continue the study as before. The interim analysis may also recommend stopping a study if there are as many infections in the vaccine group as in that of the placebos, or if we notice that the safety profile of the vaccine, in comparison with the placebo , is much more problematic.