Effectiveness of second booster compared to first booster and protection conferred by previous SARS-CoV-2 infection against symptomatic Omicron BA.2 and BA.4/5 in France

Given the evolution of the COVID-19 epidemic, protecting the most vulnerable people has been a priority objective since the beginning of the vaccination campaign. In this context, it was important to evaluate the effectiveness of vaccines distributed to this population on an ongoing basis. We therefore conducted two primary studies on monovalent vaccines, which target the original SARS-CoV-2 strain: 

• One investigating the effectiveness of the complete two-dose primary vaccination series and of the first booster against severe forms of COVID-19 linked to the Delta and Omicron BA.1 variants (Study 1)
• Another investigating the effectiveness of the second booster against symptomatic infections with Omicron BA.2 and BA.4/5 variants (Study 2), taking into account previous infections.

These studies contended with several challenges: the emergence of new variants, natural immunity, reinfections, as well as a sharp decline in the number of “unvaccinated” people who usually constitute the reference population in studies on vaccine effectiveness. We used a test-negative design, which compares the vaccination status of people with COVID-19 symptoms according to the results (positive or negative) of a diagnostic test. If the vaccine is effective, the proportion of vaccinated people is higher among SARS-CoV-2-negative individuals than among positive individuals. This method, initially developed to evaluate the effectiveness of the seasonal flu vaccine, has been widely used to evaluate the real-world effectiveness of COVID-19 vaccines in France and elsewhere. Upon the launch of the vaccination campaign in 2021, this was the method retained for all vaccine effectiveness studies conducted by Santé publique France.

While Study 1^[1] used unvaccinated people as a reference, this became very difficult in subsequent studies because most people in France were already vaccinated against COVID-19: more than 90% of people aged 50 and over have received at least a first dose of vaccine. For this reason, the reference group in Study 2^[2] consisted of people who had received a booster vaccination (following two doses of a complete primary series) 6 to 7 months before the diagnostic test included in the study. The protection measured in this study – i.e. protection provided by the second booster – is therefore additional protection to that provided by the first booster taken 6 to 7 months earlier. Thus, protection estimated at 0% here does not mean no protection, but that the second booster did not provide any additional protection compared to the first booster taken 6 to 7 months before. 

In contrast to clinical trials, there is no random draw to allocate vaccines in real-world studies. Our protocol ensures that cases (people who test positive for SARS-CoV-2) and controls (people who test negative for SARS-CoV-2) are comparable, except for vaccination status, particularly in terms of their risk behaviours and use of SARS-CoV-2 screening. Thus, we compared people (cases and controls) who lived in the same area and performed the same type of test (RT-PCR or antigen test) in the same week. The statistical analysis also takes into account other factors that could influence the vaccination status of individuals, including gender, age or the presence of comorbidities. Particular consideration was given to the time interval between the last vaccination and the diagnostic test, as well as to prior Sars-CoV-2 infections, both of which are known to influence the effectiveness of the vaccination. 

In Study 1, the effectiveness of a complete two-dose primary vaccination series with an mRNA vaccine against risk of hospital admission in subjects aged 50 years and older was estimated at 96% against the Delta variant (circulating between June and December 2021) and 92% against the Omicron variant (dominant since January 2022). This level of effectiveness applies to the first month (8-30 days) after taking the second dose of vaccine. The effectiveness against risk of admission to intensive care or death in hospital was estimated at 95% against the Delta variant and 98% against the Omicron variant. While these levels of protection were maintained at high levels over several months against the Delta variant, a decrease over time was observed against the Omicron variant, particularly in the 80+ age group. The booster dose restored high levels of protection against this variant. This study was able to demonstrate the major benefit of the booster dose during the Omicron epidemic, which is ongoing since January 2022.

Study 2 showed that, all else being equal, people 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 taken 6 to 7 months earlier. The additional protection conferred was 41%. In practice, the risk of developing SARS-CoV-2 infection was almost halved in people who had received a second booster dose compared to those who had received a first booster 6 to 7 months earlier. The study therefore confirms that booster vaccines targeting the original virus are effective against infections with Omicron BA.2 and BA.4/5, which were the dominant variants in the study. However, as with the primary vaccination series and the first booster dose, we observed a decrease in protection over time. The level of added protection at 3 to 4 months after the second booster, compared to that conferred by a first booster taken 6 to 7 months earlier, was only marginal (10%). However, it should be remembered that the protection against severe illness (requiring hospitalisation and/or leading to death), which we did not measure in this study, generally lasts longer than that against milder symptomatic forms.

Study 2 also quantified the protection conferred by an old infection against a new symptomatic SARS-CoV-2 infection in vaccinated individuals. It proved to be strong and lasting. For example, vaccinated individuals who had no prior infection recorded in the SI-DEP database were twice as likely to be infected as those who were vaccinated and infected before the onset of the Delta variant, i.e. at least 1 year before our study. For those who had been infected in the preceding 5 months, the risk of infection was divided by ten.

The bivalent vaccines on the market since September 2022 contain the messenger RNA of two strains of virus: the original virus (the same as in the first monovalent vaccines) and a strain of Omicron (BA.5 in most cases). They were designed to provide better protection against the Omicron variants in circulation. 

Also using SI-DEP and VAC-SI data, we conducted a cohort study to compare the protection against symptomatic infection conferred by a booster of bivalent vaccine with that conferred by a booster of monovalent vaccine^[3]. We followed over 135,000 people vaccinated in the same weeks for a median of 77 days. The bivalent vaccine provided 8% additional protection.

The results of these studies carried out by Santé publique France were considered by the French National Authority for Health (HAS, Haute Autorité de Santé) in the work undertaken to prepare its recommendation for the 2023 vaccination strategy. The HAS noted that the data confirms the protection conferred by a booster dose and recommended organising a booster campaign for autumn 2023 to target all people at risk of severe illness (people aged 65 years and over; infants aged 6 months and over; children, adolescents and adults with comorbidities making them more vulnerable to severe illness; immunocompromised persons; persons with any other comorbidity) and their families. In addition, the HAS is considering recommending a springtime booster for the most vulnerable people (people aged 80 years and over, immunocompromised people and people at very high risk of severe illness).