Abstract
In face of evidence of rapid waning of vaccine effectiveness against Omicron and its sub-lineages, a second booster with mRNA vaccines was recommended for the most vulnerable in France. We used a test negative design to estimate the effectiveness of the second booster relative to the first booster and the protection conferred by a previous SARS-CoV-2 infection, against symptomatic Omicron BA.2 or BA.4/5. We included symptomatic ≥60 years old individuals tested for SARS-CoV-2 in March 21-October 30, 2022. Compared to a 181–210 days old first booster, a second booster restored protection with a relative effectiveness of 41% [95%CI: 39–42%], 7–30 days post-vaccination. This gain in protection was lower than the one observed with the first booster, at equal time points since vaccination. High levels of protection were associated to previous SARS-CoV-2 infection, especially when the infection was recent and occurred when an antigenic-related variant was dominant.
Keywords: Covid-19, SARS-CoV-2, Vaccine, Immunity
1. Introduction
Since December 2021, the Omicron (B.1.1.529) variant and its subsequent sub-lineages have driven the on-going COVID-19 pandemic. This variant has been responsible for the highest number of SARS-CoV-2 infections recorded globally to date, due to its intrinsic greater transmissibility and immune escape properties. Indeed, real-world evidence has demonstrated rapid waning of vaccine effectiveness against symptomatic infection by this variant and its sub-lineages [1], [2] ; which prompted recommendations for a fourth dose (second booster).
Despite high coverage of vaccination, the important Omicron epidemic experienced by the French population resulted in a large pool of individuals with potential immunity induced by both vaccination and infection [3]. In March 2022, amidst the Omicron BA.2 epidemic, the second booster dose became recommended for the most vulnerable population including 80 years and older, from three months after receiving the first booster dose. The evolving epidemic led the French authorities to extend this booster dose to people aged 60–79 years, from six months following their first booster dose. A better understanding of the effect of the second booster, amidst the current Omicron BA.4/5 epidemic is needed going forward in the pandemic. As vaccination coverage with a first booster is now high in the French population, absolute vaccine effectiveness (compared to an unvaccinated population) was difficult to estimate.
2. Objectives
This study examined the (1) relative effectiveness of the second monovalent mRNA booster dose compared with the first booster dose, and (2) protection conferred by previous SARS-CoV-2 infection against Omicron BA.2 and Omicron BA.4/5 symptomatic infection among vaccinated individuals.
3. Methods
In France, SARS-CoV-2 testing (both RT-PCR and antigen tests) was available free of charge for all vaccinated individuals (with 2-doses primary vaccination), without prescription, during the study period. In this context, we conducted a retrospective test-negative design (TND) study on ≥60 years-old individuals with self-reported COVID-19-like symptoms, and a SARS-CoV-2 test (RT-PCR or an antigen test) performed between March 21 and October 30, 2022; period during which BA.2 and then BA.4/5 were the dominant variants in France. Eligible individuals had received at least three doses of vaccine consisting of a 2-doses primary vaccination series and one booster, and presented with no immunocompromising conditions. SARS-CoV-2 diagnostic and vaccination data were extracted from the French national information systems for all SARS-CoV-2 tests (SI-DEP), and for COVID-19 vaccine status and comorbidities (VAC-SI). Individuals with a positive test were considered as cases, and those with a negative one were controls. Cases and controls were matched in a 1:2 ratio according to the week of SARS-CoV-2 testing, type of test (antigen or RT-PCR) and area of residence (department).
Demographic characteristics as well as previous infection status data were collected. Previous SARS-CoV-2 infection was defined as a documented positive PCR or antigen test identified at least 60 days prior to the diagnostic test of inclusion, irrespective of the presence of symptoms. Variants of current infection were attributed based on (1) individual-based mutation screening performed with a multiplex RT-qPCR targeting a set of predefined mutations associated to Omicron BA.2 and Omicron BA.4/5, where available; or (2) period of circulation of a dominant variant (variant circulating at least at a 90% prevalence), determined using representative genomic surveillance data at regional level. The variant of previous infection was the dominant variant at the date of the positive test associated to the aforesaid infection. Periods during which no variant was dominant was defined as transition periods. Vaccination status was assessed at the time of the SARS-CoV-2 test. Booster 1 status was defined as complete primary vaccination (with two vaccine doses) plus one mRNA booster dose, and booster 2 status was complete primary vaccination with two mRNA booster doses.
Conditional logistic regression was used to compare the odds of testing positive for SARS-CoV-2 with one booster or two booster doses among cases and controls. The odds ratios (OR) were estimated according to the time elapsed since the last booster dose (7–30, 31–60, 61–90, 91–120, 121–150, 151–180 and 181–210 days), allowing to measure the duration of protection induced by the booster doses over time. The reference group represented individuals who received their first booster dose and had 181–210 days passed since administration of this vaccine dose (booster 1). The OR were adjusted on previous infection, sex, age group (50–79 and ≥80 years old), residence type (individual housing or Long Term Care Facilities [LTCFs]), presence of medium-risk comorbidities (yes or no), total number of SARS-CoV-2 tests performed in the last six months (used as a proxy of healthcare seeking behaviour), vaccine given as primary series and vaccine given as last booster. Previous infections were categorized according to the dominant variant at the time of these infections and the time elapsed since them. The relative vaccine effectiveness (rVE), which measures the additional protection provided by a second booster compared to the residual protection provided by a first booster was calculated as [1-adjusted OR (aOR)] × 100 when aOR ≤ 1 and as [1/aOR – 1] × 100 when aOR > 1 with 95% CI [4]. rVE was estimated for each time interval since vaccination. The same formula was used to estimate the protection conferred by a previous SARS-CoV-2 infection [5], using the OR of the same model. The estimated protection conferred by a previous infection is therefore adjusted for vaccination status and the other covariates of the model. Statistical analyses were performed using R, version 4.1.3. Further details are provided in the supplementary appendix.
4. Results
In total, 933 397 individuals were included in the analysis; of whom 456 614 (49%) SARS-CoV-2 positive (cases) were matched to 476 783 (51%) SARS-CoV-2 negative (controls) (Supplementary appendix, Fig. S2). Majority of the participants were in the 60–79 age group (80%), and had received only one booster dose (72%). Moreover, 92% had no documented previous SARS-CoV-2 infection. Antigen tests and RT-PCR accounted for 57% and 43% of the SARS-CoV-2 tests included, respectively. Fifty-one percent (51%) of positive SARS-CoV-2 tests were attributed to Omicron BA.2, 36% occurred during the period of transition from BA.2 to BA.4/5, and 13% were allocated to Omicron BA.4/5 (Fig. S3). The majority of individuals had received the mRNA BNT162b2 BioNTech/Pfizer vaccine as primary series (70%) and as inclusion booster (80%). For 20% of the individuals, the mRNA-1273 Moderna vaccine was the inclusion booster (Table 1 ).
Table 1.
Descriptive statistics of the study population.
| Participant status |
|||
|---|---|---|---|
| Variables | Overall N = 933 3971 |
Cases N = 456 6141 |
Control N = 476,7831 |
| Age group | |||
| 60–79 | 749 078 (80%) | 378 733 (83%) | 370 345 (78%) |
| 80–100 | 184 319 (20%) | 77 881 (17%) | 106 438 (22%) |
| Sex | |||
| Female | 543 645 (58%) | 256 744 (56%) | 286 901 (60%) |
| Male | 389 752 (42%) | 199 870 (44%) | 189 882 (40%) |
| Presence of comorbidities* | |||
| No | 557 973 (60%) | 290 682 (64%) | 267 291 (56%) |
| Yes | 375 424 (40%) | 165 932 (36%) | 209 492 (44%) |
| Region of residence | |||
| Auvergne-Rhône-Alpes | 112 452 (12%) | 55 582 (12%) | 56 870 (12%) |
| Bourgogne-Franche-Comté | 49 114 (5%) | 24 125 (5%) | 24 989 (5%) |
| Bretagne | 58 036 (6%) | 28 959 (6%) | 29 077 (6%) |
| Centre-Val de Loire | 33 740 (4%) | 16 593 (4%) | 17 147 (4%) |
| Corse | 4 882 (1%) | 2 348 (1%) | 2 534 (1%) |
| Grand Est | 97 568 (10%) | 47 685 (10%) | 49 883 (10%) |
| Guadeloupe | 1 176 (0%) | 581 (0%) | 595 (0%) |
| Guyane | 341 (0%) | 163 (0%) | 178 (0%) |
| Hauts-de-France | 71 263 (8%) | 34 822 (8%) | 36 441 (8%) |
| Île-de-France | 116 741 (13%) | 54 567 (12%) | 62 174 (13%) |
| La Réunion | 5 790 (1%) | 2 749 (1%) | 3 041 (1%) |
| Martinique | 975 (0%) | 477 (0%) | 498 (0%) |
| Normandie | 49 469 (5%) | 24 454 (5%) | 25 015 (5%) |
| Nouvelle-Aquitaine | 90 707 (10%) | 44 912 (10%) | 45 795 (10%) |
| Occitanie | 107 194 (11%) | 52 758 (12%) | 54 436 (11%) |
| Pays de la Loire | 53 305 (6%) | 26 478 (6%) | 26 827 (6%) |
| Provence-Alpes-Côte d'Azur | 80 642 (9%) | 39 360 (9%) | 41 282 (9%) |
| Saint-Martin | 2 (0%) | 1 (0%) | 1 (0%) |
| Healthcare worker status | |||
| No | 900 330 (99%) | 440 937 (98%) | 459 393 (99%) |
| Yes | 13 003 (1%) | 6 902 (2%) | 6 101 (1%) |
| Residence type | |||
| Individual housing | 885 228 (95%) | 444 096 (97%) | 441 132 (93%) |
| LTCFs | 48 169 (5%) | 12 518 (3%) | 35 651 (7%) |
| Vaccination status | |||
| Booster 1 | 671 817 (72%) | 335 080 (73%) | 336 737 (71%) |
| Booster 2 | 261 580 (28%) | 121 534 (27%) | 140 046 (29%) |
| Time since last vaccine dose | |||
| Booster 1 (180,210] | 184 051 (20%) | 95 646 (21%) | 88 405 (19%) |
| Booster 1 (150,180] | 152 458 (16%) | 77 701 (17%) | 74 757 (16%) |
| Booster 1(120,150] | 173 541 (19%) | 88 208 (19%) | 85 333 (18%) |
| Booster 1 (90,120] | 121 115 (13%) | 57 877 (13%) | 63 238 (13%) |
| Booster 1 (60,90] | 31 277 (3%) | 12 779 (3%) | 18 498 (4%) |
| Booster 1 (30,60] | 7 130 (1%) | 2 382 (1%) | 4 748 (1%) |
| Booster 1 [7,30] | 2 245 (0%) | 487 (0%) | 1 758 (0%) |
| Booster 2 (180,210] | 12 054 (1%) | 6 440 (1%) | 5 614 (1%) |
| Booster 2 (150,180] | 19 599 (2%) | 10 144 (2%) | 9 455 (2%) |
| Booster 2 (120,150] | 25 351 (3%) | 12 957 (3%) | 12 394 (3%) |
| Booster 2 (90,120] | 54 861 (6%) | 27 544 (6%) | 27 317 (6%) |
| Booster 2 (60,90] | 58 427 (6%) | 27 287 (6%) | 31 140 (7%) |
| Booster 2 (30,60] | 46 774 (5%) | 19 365 (4%) | 27 409 (6%) |
| Booster 2 [7,30] | 44 514 (5%) | 17 797 (4%) | 26 717 (6%) |
| Type of test | |||
| RT-PCR | 405 023 (43%) | 197 360 (43%) | 207 663 (44%) |
| Antigenic test | 528 374 (57%) | 259 254 (57%) | 269 120 (56%) |
| Number of tests in last 6 months | |||
| 0 | 436 821 (47%) | 239 560 (52%) | 197 261 (41%) |
| 1–4 | 455 847 (49%) | 206 153 (45%) | 249 694 (52%) |
| 5–9 | 37 197 (4%) | 10 228 (2%) | 26 969 (6%) |
| 10–20 | 3 532 (0%) | 673 (0%) | 2 859 (1%) |
| Number of previous infection | |||
| 0 | 862 715 (92%) | 446 769 (98%) | 415 946 (87%) |
| 1 | 69 367 (7%) | 9 717 (2%) | 59 650 (13%) |
| 2–4 | 1 315 (0%) | 128 (0%) | 1 187 (0%) |
| Variant of current infection | |||
| Omicron_BA.2 | 233 627 (51%) | 233 627 (51%) | 0 |
| Transition BA.2-BA.4_5 | 57 975 (13%) | 57 975 (13%) | 0 |
| Omicron_BA.4_5 | 165 012 (36%) | 165 012 (36%) | 0 |
| Variant of previous infection | |||
| None | 862 715 (92%) | 446 769 (98%) | 415 946 (87%) |
| Transition Alpha-Delta | 285 (0%) | 77 (0%) | 208 (0%) |
| pre-Delta | 7 648 (1%) | 2 185 (0%) | 5 463 (1%) |
| Delta | 8 196 (1%) | 1 875 (0%) | 6 321 (1%) |
| Transition Delta-BA.1 | 8 204 (1%) | 1 401 (0%) | 6 803 (1%) |
| Omicron BA.1 | 16 551 (2%) | 2 127 (0%) | 14 424 (3%) |
| Transition BA.1-BA.2 | 15 138 (2%) | 1 410 (0%) | 13 728 (3%) |
| Omicron BA.2 | 11 273 (1%) | 608 (0%) | 10 665 (2%) |
| Transition BA.2-BA.4/5 | 1 203 (0%) | 59 (0%) | 1 144 (0%) |
| Omicron BA.4/5 | 2 184 (0%) | 103 (0%) | 2 081 (0%) |
| Primary vaccination series | |||
| Pfizer monovalent | 649 567 (70%) | 319 265 (70%) | 330 302 (69%) |
| AstraZeneca | 186 797 (20%) | 91 904 (20%) | 94 893 (20%) |
| Moderna monovalent | 81 791 (9%) | 38 539 (8%) | 43 252 (9%) |
| Heterologous | 15 242 (2%) | 6 906 (2%) | 8 336 (2%) |
| Inclusion booster vaccine | |||
| Pfizer monovalent | 747 924 (80%) | 367 578 (81%) | 380 346 (80%) |
| Moderna monovalent | 185 473 (20%) | 89 036 (19%) | 96 437 (20%) |
*included obesity, diabetes, chronic renal failure, chronic obstructive pulmonary disease, respiratory failure, hypertension, and heart failure.
n (%); percentages may not total 100 due to rounding.
Estimates of the adjusted rVE and aOR by days since administration of the first and second boosters are presented in Fig. 1 and Table S1 (Supplementary appendix), respectively. Compared with individuals who received the first booster dose 181–210 days before being tested, the relative protection associated to the first booster and the second booster 7–30 days post vaccination was 64% [95% CI: 59–67%] and 41% [39–42%], respectively. A statistically significant decrease in the rVE, across time intervals since last vaccination, was observed for both booster 1 and booster 2. However, at similar vaccination time points, the gain in protection measured by the rVE offered by the second booster was lower than the protection offered by the first booster. For instance, rVE of the second booster 91–120 days ago was 10% [7–12%] whereas at the same time interval, the rVE of the first booster was 31% [29–32%] (Fig. 1).
Fig. 1.
Adjusted relative vaccine effectiveness of the second booster of mRNA COVID-19 vaccine, compared to those who received the first booster dose 181–210 days previously, against symptomatic Omicron BA.2 and BA.4/5 infection among ≥60 years and older. Error bars = 95% confidence intervals of the estimates.
Compared to people without previous infection, the more recent was the previous infection, the higher was the protection against symptomatic infection (Fig. 2 ). For instance, the adjusted protection associated with a 61–112 days old previous infection, which occurred during the Omicron BA.2 dominant period, was 96% [95%–96%] whereas a 321–467 days old previous infection from the Delta-predominant period was associated with protection of 62% [58%–66%]. Note that comparing the protection induced by the different dominant variants of previous infections can only be done when data are available at similar time intervals since previous infection. For instance, five months (≥150 days) following a previous infection, protection was higher if the previous infection occurred during the BA.2 dominant period compared to during the BA.1 period (Fig. 2, Table S1): 91% [89%–92%] vs 79% [77%–80%], respectively.
Fig. 2.
Adjusted protection associated with a previous SARS-CoV-2 infection against Omicron BA.2 and BA.4/5 symptomatic infection among ≥60 years old. Protection is estimated according to the time since previous infection and the variant dominant at the time of the previous infection. Individuals without a documented previous infection served as reference. For each variant of previous infection, participants were divided into three groups of equal size; the cut points were defined by the tertiles of time since the infection. The diamond represents the point estimate of protection for each time interval (vertically) and the median time since last infection within each third (horizontally). Rectangles around the point estimates represent the time range (horizontally), and the 95% CI of protection (vertically). Periods of transition between variants are not represented.
5. Discussion
To date, few studies have explored the relative protection gained from the second COVID-19 booster vaccines in comparison to the first booster and at equal times from vaccination. In this TND study, we found that a recent second booster dose of BNT162b2 or mRNA-1273 vaccine provided additional protection against symptomatic COVID-19 infection, relative to the residual protection of a 6-month-old (180–210 days) first booster dose. This was observed when Omicron BA.2 and BA.4/5 were dominant in France. Similar observations have been reported in recent studies from Israel [6], [7] and Canada [8]. In Israel, the rVE against infection of a second booster, compared to the first one received at least four months ago, among adults aged 60 years and older was estimated at 58% [56–60%] 7–13 days from vaccination. This VE quickly declined over time to 22% [5–36%] at 63–69 days [7]. The Canadian study also found that, compared to the first booster dose of mRNA vaccine received ≥84 days ago, the second booster offered additional protection against any SARS-CoV-2 infection and symptomatic infection, estimated at 19% [12–26%] and 31% [20–41%], respectively among long-term care residents aged ≥60 years [8]. It is important to mention that this gain in protection provided by the second booster adds to a residual protection provided by the first booster. Although in this study we could not measure the absolute VE of an old first booster compared to unvaccinated individuals, this estimate has been reported elsewhere. Link-Gelles and colleagues in the USA estimated this VE at 32% [26–38%] against laboratory-confirmed COVID-19–associated emergency department or urgent care encounters among adults ≥50 years old, ≥120 days post receiving the first booster (third vaccine dose), during the Omicron BA.2–predominant period [9].
While additional protection with the second booster dose was achieved, it decreased over time reaching levels below 10% at >90 days post vaccine administration. Indeed, waning of protection against SARS-CoV-2 infection is consistent with observations made with previous COVID-19 vaccine doses, especially amidst the Omicron epidemic [2], [10] . Nonetheless, we noted that, compared to a ≥6-month-old first booster, the gain in protection offered by the second booster was significant but lower than the protection offered by the first booster, at similar vaccination time points. Supplementary analyses showed similar patterns for both Omicron BA.2 and BA.4/5 periods of inclusion (Fig. S4), between age groups (Fig. S5), according to the types of SARS-CoV-2 test (Fig. S6), and depending on the documentation of a previous infection (Fig. S7). This moderate gain in protection may be explained by a high baseline protection conferred by the first booster dose. This hypothesis goes along data from an open-label, nonrandomized clinical study conducted in Israel among healthcare workers. The participants had received four doses of either BNT162b2 Pfizer–BioNTech or mRNA-1273 Moderna vaccines four months after the third dose in a series of three BNT162b2 doses. Results from the study suggested that three doses achieves maximal immunogenicity of mRNA vaccines; titers of vaccines induced IgG antibodies and neutralizing antibody titers were slightly higher after receiving the fourth dose, than those achieved after the third dose [11]. We may also bring forward the hypothesis of immune imprinting [12]. So far, the vaccinated population has been repeatedly stimulated with vaccines targeting the conserved regions of the ancestor virus’s spike protein, therefore enabling a strong and specific immune response against this virus and other closely related antigenic variants. In the context of immune imprinting, frequent exposure to the same antigen is to the detriment of new neutralizing responses against variant antigens. The Omicron variant differs substantially from this wild-type virus, with a greater number of mutations within the receptor-binding region [13]. A few reports have eluded to this phenomenon in the context of vaccine effectiveness against Omicron infection, in presence and in absence of previous infection [14], [15], [16]. Moreover, it has been shown in animal model that repeated boosters induce humoral and cellular immune tolerance [17]. Still, there is a need for human clinical studies to evaluate the impact of immune imprinting, amidst this evolving pandemic and the advent of new SARS-CoV-2 variants. These data would be important to inform future vaccination policies, and to understand the effects of new bivalent vaccines.
This study also showed that having experienced a recent previous infection was associated with high levels of protection against symptomatic infection, more so during the period of dominance of an antigenic-related variant. Similar observations have been previously reported in France [3], and elsewhere [5]. Interestingly, protection remained high even among individuals who experienced a non-Omicron previous infection. Protection associated with a 321–467 days old previous infection from the Delta-predominant period was 61.7% [57.5%–65.5%]. Almost two years after the previous infection, moderate protection remained among these vaccinated individuals. This observation reflects the strength of the combined effects of infection and vaccination also known as hybrid immunity [18], [19].
This analysis presents limitations to consider. Firstly, a number of symptomatic infections are not documented within SI-DEP. Two main reasons are attributed to this limitation: (1) some symptomatic individuals did not perform a SARS-CoV-2 test, and (2) others used self-administered tests, which are not captured in SI-DEP. These shortcomings may have led to an underestimation of the protection associated with previous infection. However, the TND ensures that the assessment of VE is not biased by this limit, provided that treatment-seeking behaviour does not differ between vaccinated and unvaccinated [20]. Moreover, the study considered only vaccinated people, who would have access to testing free of charge, but would have to pay for a self-administered test. Further means for controlling healthcare-seeking behaviour bias included (1) matching cases and controls by week of testing and place of residence, and (2) adjusting the models for potential confounders. Despite matching cases and controls and adjusting for potential confounders, some residual or unmeasured confounding may have remained. For example, the severity of symptoms may influence the decision for testing. Individuals with light symptoms, especially in the few days following vaccination, may not get tested whereas those with severe symptoms may do so. To limit this bias, we adjusted on time since vaccination. Moreover, the lack of data related to socio-economic status did not allow the consideration of this potential confounder, which may influence the decision to get vaccinated and access to vaccines. Lastly, both positive SARS-CoV-2 RT-PCR and antigenic tests were considered in the study, despite the difference in diagnostic sensitivity of the two assays; the diagnostic sensitivity of the tests may influence estimation of VE [20], [21]. To control for this bias, cases and controls were matched according to the type of SARS-CoV-2 test (RT-PCR or antigen test). A sensitivity analysis showed no major differences in VE estimates when the study was restricted either to RT-PCR or antigen tests (Fig. S6).
6. Conclusion
Findings from this study show additional protection with a second booster dose of monovalent mRNA vaccines, compared to a ≥6 month old first booster dose. However, the gain in protection offered by a second booster was inferior to the protection observed with a first booster at equal time since these booster doses. Moreover, in the context of an Omicron-driven pandemic, vaccination coupled with recent prior infection offer high levels of protection against subsequent Omicron infection. It will be interesting to understand the contribution of bivalent vaccines in this evolving pandemic.
Ethical statement
This study did not involve the human person. It was carried out by Santé Publique France using data collected by the Ministry of Health to manage the COVID-19 crisis. This processing of personal pseudonymised data was implemented in accordance with the legislative and regulatory prerogatives granted to Santé publique France to fulfil its public interest mission and in compliance with the provisions of the GDPR. In this context, the opinion of an ethics committee was not required.
Authors contributions.
CT, VA, JS, SV and IPC conceived and designed the study; CT and VA reviewed the literature, managed the datasets, did the statistical analysis and wrote the original draft. All authors contributed to the discussion, reviewed the manuscript and made the decision to submit for publication.
Data sharing statement
While all data used in this analysis were pseudonymised, the individual-level nature of the data used risks individuals being identified, or being able to self-identify, if it is released publicly. Requests for access to the underlying source data should be directed to Santé publique France and will be granted in accordance with the GDPR and French Law.
Funding
The study was performed as part of routine work at Public Health France.
Role of the funding source
No funders had any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. CT, VA and SV, had full access to the data and all authors made the decision to submit for publication.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We would like to thank the health care professionals and administrative teams in hospitals and biomedical laboratories, the professionals in charge of vaccinations and all those who contributed to the data management and analysis over the past three years. We would particularly like to thank Bruno Coignard and Didier Che, whose scientific and organisational support made this study possible, Daniel Levy-Bruhl, who set up the vaccine effectiveness studies in our team, Yann Le Strat, for his support in biostatistics and Charline Montagnat (Sully group) for data processing.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.vaccine.2023.03.031.
Appendix A. Supplementary material
The following are the Supplementary data to this article:
Data availability
Requests for access to the underlying source data should be directed to Santé publique France and will be granted in accordance with the GDPR and French Law.
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Supplementary Materials
Data Availability Statement
Requests for access to the underlying source data should be directed to Santé publique France and will be granted in accordance with the GDPR and French Law.