Given the evolving nature of the COVID-19 pandemic, protecting the most vulnerable individuals has been a top priority since the start of the vaccination campaign. In this context, it was important to continuously assess the effectiveness of the vaccines administered to this population. Two main studies were therefore conducted on so-called monovalent vaccines, which target the original strain of SARS-CoV-2:

• One focused on the efficacy of the full two-dose primary vaccination series and the first booster dose against severe forms of COVID-19 associated with the Delta and Omicron BA.1 variants (Study 1), and

• Another that examined the efficacy of the second booster dose against symptomatic infections linked to the Omicron BA.2 and BA.4/5 variants (Study 2), taking prior infections into account.

These studies had to address several challenges: the emergence of new variants, natural immunity, reinfections, as well as the sharp decline in the number of “unvaccinated” individuals, who typically constitute the reference population in vaccine efficacy studies. We used the so-called “test-negative design” method, which compares the vaccination status of individuals with COVID-19 symptoms based on the results (positive or negative) of the diagnostic test. If the vaccine is effective, the proportion of vaccinated individuals is higher among those who test negative for SARS-CoV-2 than among those who test positive. This method, initially developed to assess the efficacy of the seasonal flu vaccine, has been widely used to evaluate the real-world efficacy of COVID-19 vaccines in France, as elsewhere. It was selected as the method to be followed for real-world vaccine efficacy studies conducted by Santé publique France in 2021 upon the launch of the vaccination campaign.

While Study 1[1] used unvaccinated individuals as a reference group, it became very difficult to do so for subsequent studies, as there are few people in France who have not been vaccinated against COVID-19. In fact, more than 90% of individuals over the age of 50 have received at least one initial dose of the vaccine. In Study 2 [2], we therefore used as a reference group individuals who had received a booster dose (following the two doses of the initial full vaccination series) 6 to 7 months prior to the diagnostic test included in the study. The protection measured in this study—in this case, that provided by the second booster—is therefore additional protection compared to that enjoyed by people who received a first booster 6 to 7 months prior. Thus, protection estimated here at 0% does not mean there is no protection at all, but rather that the second booster did not provide additional protection compared to the first booster administered 6 to 7 months earlier.

Unlike clinical trials, in real-world studies there is no randomization to assign vaccines. Our protocol ensures that cases (people who tested positive for SARS-CoV-2) and controls (people who tested negative for SARS-CoV-2) are comparable, except for vaccination status, particularly regarding behaviors related to infection risk and the use of SARS-CoV-2 testing. Thus, we compared individuals (cases and controls) tested in the same week, residing in the same department, and who underwent the same type of test (RT-PCR or antigen test). The statistical analysis also accounts for other factors that could influence individuals’ vaccination status, such as sex, age, or the presence of comorbidities. Particular attention was paid to the time interval between the last vaccination and the diagnostic test, as well as to the presence of a prior SARS-CoV-2 infection—two factors known to influence the efficacy conferred by vaccination.

In Study 1, the efficacy of the full primary vaccination series—consisting of two doses of an mRNA vaccine—in reducing the risk of hospitalization among individuals aged 50 and older was estimated at 96% against the Delta variant (circulating between June and December 2021) and at 92% against the Omicron variant (which has become the dominant variant since January 2022), during the first month (8–30 days) after the second vaccine dose. Efficacy against the risk of hospitalization in critical care or in-hospital death was estimated at 95% against the Delta variant and 98% against the Omicron variant. While these levels of protection remained high over several months against the Delta variant, a decline over time, particularly among those aged 80 and older, was observed against the Omicron variant. The booster dose restored high levels of protection against this variant. This study demonstrated the significant benefit of the booster during the Omicron-driven surge, which has persisted since January 2022.

Study 2 demonstrated that, all else being equal, individuals who received a second booster 7 to 30 days before the diagnostic test included in the study were better protected against symptomatic infection than those whose last vaccination was a first booster administered six to seven months prior. This additional protection amounted to 41%. In practice, people who had received a second booster had a risk of developing a SARS-CoV-2 infection that was nearly halved compared to those who had received a first booster 6 to 7 months prior. The study thus confirms the effectiveness of booster shots—using vaccines targeting the original virus—against infections with Omicron BA.2 and BA.4/5, which were the dominant variants during the study. However, as with the primary vaccination series and the first booster, we observe a decline in protection over time. Three to four months after the second booster, the increase in protection, compared to a first booster administered 6 to 7 months earlier, was only marginal (10%). It should be noted, however, that protection against severe disease (requiring hospitalization and/or resulting in death), which we did not measure in this study, is generally more durable than protection against less severe symptomatic forms.

Study 2 also quantified the protection conferred by a previous infection against a new symptomatic SARS-CoV-2 infection in vaccinated individuals. It proved to be strong and long-lasting. For example, vaccinated individuals who were infected before the emergence of the Delta variant—that is, at least one year prior to our study—had a risk of infection that was half that of vaccinated individuals with no reported infection in the SI-DEP database. For individuals who had been infected five months or less prior, the risk of infection was reduced by a factor of 10.

The bivalent vaccines that have been available since September 2022 contain messenger RNA from two viral strains: that of the original virus—the same as in the first, so-called monovalent vaccines—and that of an Omicron strain (BA.5 in most cases). They were designed to provide better protection against circulating Omicron variants.

Using data from SI-DEP and VAC-SI, we conducted a cohort study to compare the protection against symptomatic infection provided by a booster dose of these bivalent vaccines versus a booster dose of monovalent vaccines [3]. We followed, for a median duration of 77 days, more than 135,000 people vaccinated during the same weeks. The bivalent vaccine provided 8% additional protection.

The results of these studies conducted by Santé publique France were taken into account by the Haute Autorité de Santé (HAS) during its preparatory work prior to the publication of its 2023 vaccination strategy recommendation. The HAS notes that the data confirm the protection provided by a booster dose and recommends organizing, in the fall of 2023, a booster campaign for all individuals at risk of severe disease (people aged 65 and older, infants aged 6 months and older, children, adolescents, and adults with comorbidities who are at higher risk of severe disease, immunocompromised individuals, and people with any other comorbidities) and their close contacts. In addition, it plans to recommend a booster in the spring for the most vulnerable (people aged 80 and older, immunocompromised individuals, and those at very high risk of the disease).