The most frequently asked questions about candidate vaccines against SARS-CoV-2
Comments of Natalia Vostokova, PhD, IPHARMA Chief Operating Officer, on the development of vaccines against COVID-19 from Anna Remish's article "The race for salvation: Are coronavirus vaccines safe?".
Anna Remish (AR): Many are afraid that, in a rush, the coronavirus vaccines will not be properly tested. People believe that you cannot start a mass vaccination without testing a new vaccine for years. How reasonable are these fears and is it really necessary to "hold back" on new vaccines with at least a 1-year surveillance over the vaccinated volunteers?
Natalia Vostokova (NV): To assess the efficacy and safety of the COVID-19 vaccine, WHO has developed a Phase III clinical trial guideline. The trial should have a double-blind placebo-controlled design. The main measurement (primary endpoint) is the incidence of COVID-19 in volunteers who received the study vaccine or placebo. The important thing to understand is that no vaccine can be 100% effective in all people, so the effectiveness of vaccination is assessed by reduction in incidence rate compared to placebo.
WHO proposes the 50% vaccine efficacy to be the baseline parameter for the statistical hypothesis of the study. For that to happen, a sufficient number of volunteers must be enrolled so that 150 cases of COVID-19 could be registered. It may be hundreds or thousands of people, depending on how quickly and widely the disease spreads. The required duration of the follow-up period in the study also depends on this.
If a required number of volunteers is included in the midst of the active infection spread, three to six months follow-up will be sufficient for an assessment. The vaccine will be considered effective if the incidence of COVID-19 would be twice lower for the vaccinated versus the unvaccinated, i.e., out of 150 cases, the ratio of volunteers who received the vaccine or placebo would be 50:100 (or less). Of course, we all hope that an effective vaccine will be able to completely prevent the transmission of infection in society, and that is why it is necessary that the vast majority of people get the vaccine, otherwise even an effective vaccine will not achieve this goal.
AR: From a vaccine safety perspective, is it appropriate to save time by running parallel study instead of consecutive (for example, starting Phase II just a couple of weeks earlier than Phase III)?
NV: The purpose of Phase II study is the dose selection and optimal vaccination schedule that will allow for the development of strong immunity. For this, different parameters of the vaccine potency are assessed at certain time intervals (in particular, how the antibody titer changes over time). The immune system responds differently to vaccination in different people, so the study should have a double-blind and placebo-controlled design to distinguish the variability in the immune response within each vaccination schedule from significant differences between them. This allows to select an optimal dose regimen for further Phase III clinical study - after all, even a potentially effective vaccine will not work if the dose and vaccination schedule are selected incorrectly. This preliminary assessment takes several weeks to several months and can start from the first administration of the vaccine to volunteers within Phase I.
As for the safety, it is assessed at all stages of the clinical development of a vaccine and is a key factor in making a decision of its further study or registration. In the WHO recommendations for candidate vaccines against COVID-19, the main period for collecting data on adverse reactions is the first 14 days following each vaccination (however, the safety data are collected longer - up to 28 days post-vaccination). At the same time, when assessing safety, in addition to possible adverse reactions, it is important to study the risk of an unintentional increase in the incidence or severity of COVID-19 in the vaccinated. For this assessment, WHO recommends the Independent Data Monitoring Committee to regularly assess COVID-19 cases in volunteers receiving vaccine or placebo.