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. 2023 Jan 11;20(1):e1004156. doi: 10.1371/journal.pmed.1004156

Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland: A test-negative design case–control study

Thiago Cerqueira-Silva 1,2,‡, Syed Ahmar Shah 3,‡, Chris Robertson 4,5,‡, Mauro Sanchez 6, Srinivasa Vittal Katikireddi 4,7, Vinicius de Araujo Oliveira 2,8, Enny S Paixão 9, Igor Rudan 3, Juracy Bertoldo Junior 2,8, Gerson O Penna 6, Neil Pearce 9, Guilherme Loureiro Werneck 10,11, Mauricio L Barreto 2,8, Viviane S Boaventura 1,2,‡, Aziz Sheikh 3,‡, Manoel Barral-Netto 1,2,8,‡,*
Editor: Amitabh Bipin Suthar12
PMCID: PMC9879484  PMID: 36630477

Abstract

Background

Brazil and Scotland have used mRNA boosters in their respective populations since September 2021, with Omicron’s emergence accelerating their booster program. Despite this, both countries have reported substantial recent increases in Coronavirus Disease 2019 (COVID-19) cases. The duration of the protection conferred by the booster dose against symptomatic Omicron cases and severe outcomes is unclear.

Methods and findings

Using a test-negative design, we analyzed national databases to estimate the vaccine effectiveness (VE) of a primary series (with ChAdOx1 or BNT162b2) plus an mRNA vaccine booster (with BNT162b2 or mRNA-1273) against symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes (hospitalization or death) during the period of Omicron dominance in Brazil and Scotland compared to unvaccinated individuals. Additional analyses included stratification by age group (18 to 49, 50 to 64, ≥65). All individuals aged 18 years or older who reported acute respiratory illness symptoms and tested for SARS-CoV-2 infection between January 1, 2022, and April 23, 2022, in Brazil and Scotland were eligible for the study. At 14 to 29 days after the mRNA booster, the VE against symptomatic SARS-CoV-2 infection of ChAdOx1 plus BNT162b2 booster was 51.6%, (95% confidence interval (CI): [51.0, 52.2], p < 0.001) in Brazil and 67.1% (95% CI [65.5, 68.5], p < 0.001) in Scotland. At ≥4 months, protection against symptomatic infection waned to 4.2% (95% CI [0.7, 7.6], p = 0.02) in Brazil and 37.4% (95% CI [33.8, 40.9], p < 0.001) in Scotland. VE against severe outcomes in Brazil was 93.5% (95% CI [93.0, 94.0], p < 0.001) at 14 to 29 days post-booster, decreasing to 82.3% (95% CI [79.7, 84.7], p < 0.001) and 98.3% (95% CI [87.3, 99.8], p < 0.001) to 77.8% (95% CI [51.4, 89.9], p < 0.001) in Scotland for the same periods. Similar results were obtained with the primary series of BNT162b2 plus homologous booster. Potential limitations of this study were that we assumed that all cases included in the analysis were due to the Omicron variant based on the period of dominance and the limited follow-up time since the booster dose.

Conclusions

We observed that mRNA boosters after a primary vaccination course with either mRNA or viral-vector vaccines provided modest, short-lived protection against symptomatic infection with Omicron but substantial and more sustained protection against severe COVID-19 outcomes for at least 3 months.

In a test-negative design case-control study, Dr. Thiago Cerqueira-Silva and colleagues, investigate the effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland.

Author summary

Why was this study done?

  • Brazil and Scotland have been offering boosters for the population that received two doses of vaccines against the coronavirus that causes Coronavirus Disease 2019 (COVID-19). However, after Omicron (a SARS-CoV-2 variant) emerged, both countries reported a high number of COVID-19 cases despite accelerating their booster programs.

  • Knowledge about the duration of the protection offered by the booster doses is essential to guide public health recommendations.

What did the researchers do and find?

  • We analyzed national databases from Brazil and Scotland between January and April 2022 to estimate the protection offered by mRNA booster doses in individuals who received a primary series of viral vector or mRNA anti-COVID-19 vaccines.

  • For individuals that received primary series of viral vector vaccine plus mRNA booster, from 14 to 29 days to ≥4 months after the booster dose, vaccine effectiveness (VE) against symptomatic infection decreased significantly in Brazil from 51.6%, 95% confidence interval (CI): [51.0, 52.2], to 4.2% (95% CI: [0.7, 7.6], p = 0.02) and in Scotland from 67.1% (95% CI [65.5, 68.5], p < 0.001) to 37.4% (95% CI [33.8, 40.9], p < 0.001).

  • In these periods, a slight decrease in VE was observed against severe outcomes in Brazil from 93.5% (95% CI [93.0, 94.0], p < 0.001) to 82.3% (95% CI [79.7, 84.7], p < 0.001) and in Scotland from 98.3% (95% CI [87.3, 99.8], p < 0.001) to 77.8% (95% CI [51.4, 89.9], p < 0.001). Similar results were obtained with a homologous booster after a primary series of mRNA vaccines.

  • Similar findings in two very different countries allow us to draw reliable results because of potential sources of bias in effectiveness studies, such as differences in testing behavior and unmeasured characteristics between vaccinated and unvaccinated individuals, which are unrelated in the two countries.

What do these findings mean?

  • Modest, short-lived protection was observed against symptomatic infection caused by the Omicron variant after two doses of either vector viral or mRNA vaccine plus a booster dose with mRNA vaccine. However, protection against hospitalization or death was substantial for at least 3 months.

Introduction

The effectiveness of available Coronavirus Disease 2019 (COVID-19) vaccines may differ by variants of concern (VOCs) and by waning immunity. Before the emergence of the Omicron VOC, real-world vaccine effectiveness (VE) studies had reported substantial protection against symptomatic infection and severe outcomes (i.e., hospitalization and death) [1–3]. However, the protection offered by COVID-19 vaccines has been shown to wane over time [4,5], prompting many countries to provide booster doses [6]. With Omicron’s emergence and rapid spread, the booster program was expedited and expanded in several countries. A few studies have evaluated the protection offered after the booster, although with conflicting results [7–9].

The available, still limited, body of evidence indicates a rapid waning of protection against symptomatic infection offered by an mRNA booster after a homologous primary series [7,8,10,11]. Findings are more conflicting concerning the potential waning of protection against severe outcomes. After three doses of mRNA vaccine, sustained effectiveness against hospital or intensive care unit (ICU) admission was reported in different studies, including young and elderly individuals within 2 months after booster [8,9,12]. At the same time, another study has demonstrated a significant waning of protection against emergency department visits and hospitalizations 4 months after the third dose [7]. These studies need more data about the medium- and longer-term effectiveness of heterologous schemes and provide limited insights about severe events across age groups. Data on the duration of protection against severe outcomes in boosted individuals by age group are crucial to guide health policies about vaccination programs.

Brazil and Scotland present similarities in vaccination programs (vaccine type used for primary series and booster) and the speed of Omicron spread. Both countries have been offering BNT16b2 or ChAdOx1 as a primary series to all adults and an mRNA booster dose, i.e., BNT16b2 in Brazil and either BNT16b2 or mRNA-1273 in Scotland. Additionally, these countries have reported a rapid surge and dominance of the Omicron variant [13]. The similarities in vaccine administration between Brazil and Scotland, coupled with essential differences in several potential confounders (such as age structure, the timing of delivery to different age groups, and healthcare characteristics such as access to hospitals), offer an opportunity to undertake robust national analyses on the duration of VE during the Omicron era. We aimed to assess the extent and duration of protection against Omicron-associated symptomatic infection and severe outcomes (i.e., COVID-19 hospitalization and death) after an mRNA booster dose in individuals of different age groups who received either BNT16b2 or ChAdOx1 for their primary vaccination series.

Methods

Study design, population, and data sources

This study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S2 Appendix). We undertook a test-negative design (TND) case–control study to estimate VE for protection against symptomatic infection and severe COVID-19 outcomes. TND is a type of case–control study that uses population test results, with the positive tests being the cases and the negative tests being the controls. It is ideally suited to situations where not everyone in a population is being tested because the factors that influence being tested will apply to both those who tested positive and those who tested negative [14]. Cases were defined as symptomatic individuals with a positive test (reverse transcriptase polymerase chain reaction (RT-PCR) or lateral flow for Brazil and RT-PCR for Scotland) and controls as symptomatic individuals with a negative test. In both countries, symptoms were assessed by self-report. Only the first positive test during the study period was included for each case, and for controls, only the first negative test was included. Controls included individuals with no record of a positive test during the study period.

All individuals aged 18 years or older who reported acute respiratory illness symptoms and tested for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection between January 1, 2022, and April 23, 2022, in Brazil and Scotland were eligible for the study (Fig B in S1 Appendix). We excluded the following: (i) individuals who received different vaccines for the second dose from the first; (ii) individuals whose time interval between the first and second doses was less than 14 days; (iii) individuals with less than 115 days between the second and booster doses (therefore a deviation from the official recommendation for Brazil); (iv) tests with missing information of age, sex, city of residence or sample collection date; and (v) sample specimen collection more than 10 days after symptoms onset.

The data in Brazil came from three deterministically linked national structured administrative databases provided by the Ministry of Health: COVID-19 Vaccination Campaign (SI-PNI); Acute Respiratory Infection Suspected Cases (e-SUS-Notifica); and Severe Acute Respiratory Infection/Illness (SIVEP-Gripe). All COVID-19 vaccine doses in Brazil are provided free of charge by the Ministry of Health. All suspected and confirmed cases of COVID-19 must be reported in the e-SUS-Notifica. Regardless of etiology, all severe acute respiratory illness cases must be notified in the SIVEP surveillance system. Therefore, these three databases should provide 100% countrywide coverage of all reported cases [15]. No detailed definition of comorbidities and race in these databases was provided.

The data in Scotland came from the EAVE II platform that brings together datasets on 5.4 million people providing around 99% countrywide coverage [5]. This platform deterministically linked multiple national datasets, including primary healthcare, laboratory, SARS-CoV-2 testing, vaccinations, death, and secondary care data. In both countries, data were anonymized and hosted within secure analytical environments previously described [5].

Exposures, confounders, and outcomes

The primary exposure was the administration of a COVID-19 vaccine booster dose. The vaccines considered in this study were a homologous series (first and second dose) of either BNT16b2 or ChAdOx1 and an mRNA booster dose (BNT16b2 in Brazil; BNT16b2 or mRNA-1273 in Scotland). We classified exposure in periods as time-varying to allow us to assess waning, stratified by primary series and booster type. In both countries, the exposure periods were unvaccinated, first dose (0 to 13 days, 14 days to 1 month, 2 to 5 months, ≥6 months), second dose (0 to 13 days, 14 days to 1 month, 2 to 4 months, ≥ 5 months), and a booster dose (0 to 13 days, 14 to 29 days, 1 month, 2 months, 3 months, and ≥ 4 months).

We used the unvaccinated individuals as the reference group in both countries to estimate VE. For both countries, we adjusted for the following potential confounders: age (5-year bands), sex, and socioeconomic position (Brazil: Brazilian Municipality Deprivation Index; Scotland: Scottish Index of Multiple Deprivation, both deprivation indexes used national cutoffs to define the quintiles), number of medical comorbidities (Brazil-Diabetes Mellitus, obesity, immunosuppression, chronic respiratory disease, cardiac disease, and chronic kidney disease) or number and types of comorbidities commonly associated with COVID-19 illness based on the QCOVID risk group (Scotland) (Table B in S1 Appendix) [16], state of residence (Brazil) or geographic area (Scotland), and previous infection (none, 3 to 5 months ago, 6 to 12 months, and >1 year), calendar time was included as the week of sample collection, and healthcare worker in Brazil and number of previous RT-PCR in Scotland (as a proxy for healthcare worker). In Scotland, we additionally adjusted for the residential settlement type (6 categories, from large urban to small remote rural areas) and household size. QCOVID risk groups are characteristics used in the QCOVID algorithm to predict the risk of hospital admission and death due to COVID-19 [16].

The two outcomes of interest were symptomatic SARS-CoV-2 infection. In Brazil, severe COVID-19 cases were defined as COVID-19 hospital admission or death. COVID-19 hospitalization was described as a positive specimen being collected up to 14 days before to 3 days after the hospital admission; cases of COVID-19 death were defined as death occurring within 28 days of the positive sample collection date. In Scotland, severe confirmed COVID-19 cases were defined as admissions to hospital or death within 28 days following a positive specimen where COVID-19 was explicitly mentioned in any place on the admission record or death certificate. Severe COVID-19 cases were defined as either (1) confirmed severe COVID-19 cases; (2) any admission to hospital within 14 days after or up to 2 days before a positive test; or (3) any death within 28 days following a positive specimen and so is a broader definition than confirmed severe cases. In our analysis, we used severe confirmed COVID-19 cases in Scotland.

Statistical analysis

The prospective statistical plan is provided in the S3 Appendix. We applied binomial logistic regression to estimate the odds ratio (OR) and the associated 95% confidence intervals (CIs) of vaccination in cases compared to controls. VE was defined as (1 − OR) * 100. Analyses were conducted by primary vaccine series type (BNT16b2 or ChAdOX1) and age group (18 to 49, 50 to 64, ≥65) in both countries. In Scotland, we also stratified by mRNA booster type (BNT16b2, or mRNA-1273); Brazil’s only mRNA vaccine was BNT162b2. In Scotland, we did not stratify by age group in the analysis of severe outcomes due to the small number of events. In Brazil, only individuals vaccinated with ChAdOx1 as primary series were analyzed in the ≥65 years age group due to the relatively small numbers of vaccinated individuals with BNT162b2 in this group.

For sensitivity analysis, we repeated the models used in the principal analysis using the individuals with a second dose without a booster dose as the comparison group (instead of the unvaccinated group), including a term of the month of the second dose to control for the potential waning of effectiveness. We also performed an exploratory analysis in Brazil using only individuals with a previously confirmed infection to assess the possible under-ascertainment bias of past infections. All p-values are two-sided and determined through Wald test. All analyses were undertaken within secure analytical environments, and the analyses were carried out using R statistical software (versions 3.6.1 and 4.1.1).

Ethical and other approvals

For Brazil, ethics approvals were obtained from the Brazilian National Commission in Research Ethics (CONEP approval number: 4.921.308). The National Research Ethics Service Committee in Scotland, Southeast Scotland 02 (reference number: 12/SS/0201) and Public Benefit and Privacy Panel for Health and Social Care (reference number: 1920–0279) approved the study.

Results

From January 01, 2022, to April 23, 2022, 5,832,210 individuals (Brazil: 5,276,385; Scotland: 555,825) were analyzed, and the median age and sex ratio were similar among cases and controls (Table 1 and Table A in S1 Appendix). Most of the tests performed in Brazil during the study period were positive (3,009,052; 57.0%), slightly elevated in unvaccinated individuals (203,964; 61.7%) and vaccinated (2,805,088; 56.7%). In Scotland, 352,015 (63.3%) tests were positive, more frequent in unvaccinated individuals (38,988; 74.6%) than in those vaccinated (313,027; 62.2%) (Table 1 and Tables A, C, and D in S1 Appendix).

Table 1. Characteristics of individuals tested for SARS-CoV-2 in Brazil and Scotland.

Brazil Scotland
Characteristic–n(%) Cases, N = 3,011,812 Controls, N = 2,269,774 Cases, N = 352,015 Controls, N = 203,810
Age group–years
18–49 2,189,355 (72.7) 1,680,102 (74.0) 244,517 (69.5) 136,390 (66.9)
50–64 692,693 (23.0) 494,404 (21.8) 82,904 (23.6) 50,109 (24.6)
≥ 65 129,764 (4.3) 95,268 (4.2) 24,594 (7.0) 17,311 (8.5)
Sex-Female 1,754,321 (58.2) 1,342,774 (59.2) 196,485 (55.8) 125,056 (61.4)
Test type
Antigen 2,458,769 (81.6) 1,954,203 (86.1) - -
RT-PCR 553,043 (18.4) 315,571 (13.9) 352,015 (100.0) 203,810 (100.0)
No. comorbidities or QCOVID Risk
0 2,755,169 (91.5) 2,046,435 (90.2) 226,394 (64.3) 122,253 (60.0)
1 206,214 (6.8) 178,454 (7.9) 94,752 (26.9) 58,481 (28.7)
2 42,373 (1.4) 37,576 (1.7) 23,396 (6.7) 16,809 (8.2)
≥3 8,056 (0.3) 7,309 (0.3) 6,832 (2.0) 6,267 (3.1)
Deprivation Index
1 (Least) 939,579 (31.2) 792,447 (34.9) 65,536 (18.6) 42,071 (20.6)
2 560,955 (18.6) 407,162 (17.9) 67,242 (19.1) 41,989 (20.6)
3 589,431 (19.6) 425,703 (18.8) 65,183 (18.5) 38,394 (18.8)
4 581,790 (19.3) 388,683 (17.1) 74,900 (21.3) 40,838 (20.0)
5 (Most) 339,183 (11.3) 255,181 (11.2) 79,154 (22.5) 40,518 (19.9)
(Missing) 874 (0.0) 598 (0.0) - -
Previous SARS-CoV-2 Infection
Not 2,808,497 (93.2) 2,020,509 (89.0) 316,843 (90.0) 167,041 (82.0)
3–6 months ago 9,871 (0.3) 16,766 (0.7) 10,874 (3.1) 15,345 (7.5)
6–12 months ago 106,687 (3.5) 134,347 (5.9) 12,274 (3.5) 11,548 (5.7)
>1 year ago 86,757 (2.9) 98,152 (4.3) 12,024 (3.4) 9,876 (4.8)
Vaccination Status
    One dose–ChAdOx1 90,069 (3.0) 61,823 (2.7) 2,307 (0.6) 1,026 (0.5)
    One dose–BNT162b2 120,949 (4.0) 111,999 (4.9) 8,193 (2.3) 3,021 (1.5)
    Two doses–ChAdOx1 1,203,551 (40.0) 696,531 (30.7) 27,908 (7.9) 10,807 (5.3)
    Two doses–BNT162b2 851,007 (28.3) 711,679 (31.4) 62,285 (17.7) 26,746 (13.1)
    Three doses–BNT162b2 69,628 (2.3) 87,694 (3.9) 106,588 (30.3) 75,415 (37.0)
    Three doses–ChAdOx1 472,644 (15.7) 473,369 (20.9) 103,407 (29.4) 71,399 (35.0)
    Four doses–ChAdOx1 - - 1159 (0.3) 683 (0.4)
    Four doses–BNT162b2 - - 574 (0.1) 330 (0.1)
    Unvaccinated 203,964 (6.8) 126,679 (5.6) 38,988 (11.1) 13,250 (6.5)
Hospitalization 38,284 (1.3) 22,596 (1.0) - -
Death 12,270 (0.4) 4,985 (0.2) - -
Severe outcome 40,522 (1.3) 23,773 (1.0) 1,375 (0.4) 372 (0.2)
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RT-PCR, reverse transcriptase polymerase chain reaction; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2.

Compared to unvaccinated individuals

In Brazil, a primary course of ChAdOx1 and a BNT16b2 booster (ChAdOx1-BNT162b2) dose led to an estimated VE against symptomatic infection of 51.6% (95% CI [51.0, 52.2], p < 0.001) after 14 to 29 days, waning to 4.2% (95% CI [0.7, 7.6], p = 0.02) at ≥4 months after the booster dose. The VE of a primary course of BNT162b2 and a BNT162b2 booster (BNT162b2-BNT162b2) was 44.6% (95% CI [43.4, 45.8], p < 0.001) at 14 to 29 days, waning to −11.8% (95% CI [−35.9, 8.0], p = 0.26) at ≥4 months past the booster dose. (Fig 1 and Table E in S1 Appendix).

Fig 1. Estimated VE against symptomatic SARS-CoV-2 infection in Brazil and Scotland, overall and stratified by age group.

Fig 1

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The square represents the estimated VE of the booster dose after the primary series with ChAdOx1, and the circle represents the booster dose after the primary series with BNT162b2. Green represents the booster dose with BNT162b2 and blue with mRNA-1273. Error bars represent the 95% Wald CI. CI, confidence interval; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; VE, vaccine effectiveness.

The estimates of VE against severe outcomes of ChAdOx1-BNT162b2 peaked in Brazil at 93.5% (95% CI [93.0, 94.0], p < 0.001) at 14 to 29 days and 82.3% (95% CI [79.7, 84.7], p < 0.001) after ≥4 months. The VE of a BNT162b2-BNT162b2 was 92.7% (95% CI [91.0, 94.0], p < 0.001) at 14 to 29 days and 74.1% (95% CI [9.1, 92.6], p = 0.03) at ≥4 months (Fig 2 and Table F in S1 Appendix).

Fig 2. Estimated VE against severe COVID-19 (hospitalization or death) in Brazil and Scotland, stratified by age groups.

Fig 2

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The square represents the estimated VE of the booster dose after the primary series with ChAdOx1, and the circle represents the booster dose after the primary series with BNT162b2. Green represents the booster dose with BNT162b2 and blue with mRNA-1273. The error bar represents the 95% Wald CI. CI, confidence interval; COVID-19, Coronavirus Disease 2019; VE, vaccine effectiveness.

Scotland had a similar pattern for both booster vaccines (BNT162b2 or mRNA-1273). After the primary series of ChAdOx1, the VE peak at 98.3% (95% CI [87.3, 99.8], p < 0.001) 14 to 29 days past booster dose for ChAdOx1-BNT162b2 and 94.4% (95% CI [87.7, 97.5], p < 0.001) for ChAdOx1-mRNA-1273 in the same period, declining to 77.8% (95% CI [51.4, 89.9], p < 0.001) and 76.0% (95% CI [59.3, 85.9], p < 0.001) at ≥4 months, respectively. (Fig 2 and Table F in S1 Appendix).

Effectiveness by age group

In Brazil, the VE against symptomatic infection of ChAdOx1-BNT162b2 and BNT162b2-BNT162b2 presented values close to 50% in all age groups at 14 to 29 days but declined more sharply in the younger (18 to 49 years), with no protection in this age group ≥4 months. However, the relative VE of both ChAdOx1-BNT162b2 and BNT162b2-BNT162b2 exhibited a similar decline in all age groups ≥4 months after the booster dose. In the exploratory analysis using only individuals with a previously confirmed infection, the ChAdOx1-BNT162b2 group presented a VE close to 70% at 14 to 29 days past booster dose in all age groups, declining, to a lesser degree than the primary analysis, to levels close to 20%. Unlike Brazil, the VE against symptomatic infection in Scotland decreased more in the older groups than the younger ones. (Fig 1 and Table E in S1 Appendix).

The VE of ChAdOx1-BNT162b2 against severe outcomes in all age groups peaked around 90% at 14 to 29 days past and stayed higher than 80% past 4 months after the booster dose. The VE by age group of BNT162b2-BNT162b2 was like the ChAdOx1. (Fig 2 and Table E in S1 Appendix). In Scotland, due to the small number of severe COVID-19 cases, we did not perform the stratified analysis by age group for this outcome.

Effectiveness of the second booster dose

The analysis of VE of the second booster dose was conducted only in Scotland due to insufficient numbers in Brazil. The VE at 7 to 29 days, after a second booster with BNT162b2, in individuals with a primary course of ChAdOx1 was 40.6% (95% CI [20.9, 55.4], p < 0.001); in the case of a second booster with mRNA-1273, the VE was 47.5% (95% CI [21.5, 64.9], p = 0.002). Regarding individuals with a primary course of BNT162b2, the VE after 7 to 29 days after a second booster was 61.1% (95% CI [43.6, 73.2], p < 0.001) in the case of BNT162b2 booster and 69.2% (95% CI [46.5, 82.3], p < 0.001) for mRNA-1273 booster. The comparison against individuals with only two doses provided similar results. (Table E in S1 Appendix).

Compared to individuals with only the primary course (two doses)

In Brazil, the relative VE of ChAdOx1-BNT162b2 compared to individuals with only two doses of ChAdOx1 against symptomatic infection was 50.9% (95% CI [50.4, 51.4], p < 0.001) after 14 to 29 days, waning to 7.0% (95% CI [3.8, 10.1], p < 0.001) at ≥4 months after the booster dose. The relative VE of a BNT162b2-BNT162b2 compared to only the primary course with BNT162b2 was 40.5% (95% CI [39.3, 41.7], p < 0.001) at 14 to 29 days, waning to 9.7 (95% CI [−9.6, 25.6], p < 0.001) at ≥4 months after the booster dose. (Table G in S1 Appendix).

In Brazil, the relative VE against severe outcomes of ChAdOx1-BNT162b2 was 79.0% (95% CI [77.3, 80.6], p < 0.001) at 14 to 29 days and waned to 59.4% (95% CI [53.3, 64.7], p < 0.001) after ≥4 months. The relative VE of BNT162b2-BNT162b2 was 54.6% (95% CI [43.9, 63.2], p < 0.001), and 38.2% (95% CI [−125.0, 83.0], p = 0.47) at ≥4 months after the booster dose. The relative VE of ChAdOx1-BNT162b2 peaked around 80% in all age groups, declining to 68.8% (95% CI [43.5, 82.8], p < 0.001), 55.8% (95% CI [31.2, 71.7], p < 0.001) and 56.2% (95% CI [48.7, 62.5], p < 0.001) in the 18 to 49, 50 to 64, and ≥65 years, respectively. (Table H in S1 Appendix).

In Scotland, the relative VE of ChAdOx1-BNT162b2 against symptomatic infection was 63.5% (95% CI [61.4, 64.7], p < 0.001) after 14 to 29 days, waning to 28.8% (95% CI [23.8, 33.5], p < 0.001) at ≥4 months after the booster dose. The relative VE of a BNT162b2-BNT162b2 was 62.7% (95% CI [61.0, 64.4], p < 0.001) at 14 to 29 days, waning to 29.1% (95% CI [24.0, 33.2], p < 0.001) at ≥4 months after the booster dose. The schemas with mRNA-1273 exhibited similar values. (Table G in S1 Appendix) The relative VE of booster doses in individuals with ChAdOx1 as primary series against severe outcomes peaked at 85.2% (95% CI [67.3, 93.3], p < 0.001) for BNT162b2 booster and 95.5% (95% CI [67.3, 99.4], p = 0.002) for mRNA-1273 booster, decreasing to 54.9% (95% CI [14.2, 76.3], p = 0.02) for BNT162b2 and 59.3% (95% CI [3.6, 82.8], p = 0.04) for mRNA-1273 past 4 months after the booster. A similar pattern was found for individuals with BNT162b2 as primary series but with less precise estimates. (Table H in S1 Appendix).

Discussion

Following a homologous primary series of BNT16b2 or ChAdOx1 vaccine, mRNA boosters (BNT16b2 or mRNA-1273) provided substantial protection against severe COVID-19 cases during the predominance of Omicron variant for at least 3 months. However, there was only moderate protection against symptomatic infection at 14 to 29 days after the booster dose administration, which sharply decreased by ≥4 months.

Our results are comparable to previous observational studies during the Omicron period, which reported the waning effectiveness of mRNA boosters against symptomatic infection. Protection against infection is modest following the booster dose and quickly decreases 4 weeks post-booster [10,11]. Older individuals experienced a faster waning than younger people [4,17]. However, we found a more pronounced waning against symptomatic infection in the younger age groups in Brazil and a comparable waning in all age groups in Scotland.

The finding of temporary protection against symptomatic infection is consistent with neutralization data, suggesting the need for a third dose to elicit antibodies with neutralizing activity against Omicron and decaying titers over time [18,19]. Neutralizing antibody titers seem to increase again early after a fourth dose, but the duration remains unknown [20]. Observational studies evaluating the effect of vaccination on previously infected individuals reported that antibody levels peaked after three immune stimuli, either by vaccine or infection, without any significant increment after a fourth stimulus [21,22]. On the other hand, cellular immunity seems to stay robust against the Omicron variant after 3 months [23]. It plays a significant role in protecting against severe disease [24,25]. It likely will stay highly effective against variants of the SARS-CoV-2 virus due to the capacity of T cells to still recognize mutated epitopes from SARS-CoV-2 [23,25,26]. Consistent with data on cellular immunity, we observed a slight waning of protection against severe outcomes in the Omicron period. A fourth dose seems to increase the protection against severe illness but not against infection in individuals aged ≥60 years [27]. We found similar levels of protection against symptomatic infection in individuals with one and two booster doses. Together, these data suggest that while humoral response and VE against infection seem to be highly affected by the Omicron variant, a limited impact is observed on cellular immunity and protection against severe disease.

We analyzed the waning by age group due to the influence of immunosenescence in VE. We observe sustained protection against severe outcomes and a slight decline in protection in individuals aged ≥65 years, represented by the decrease in the last period in both comparisons: against unvaccinated individuals and individuals with only two doses of vaccine. Different age structures may have contributed to the apparently contradictory results observed in some studies that have addressed the duration of protection of mRNA booster dose against severe disease. For example, there was high and sustained protection (over 80% VE) at ≥7 weeks after booster and no evidence of waning in Qatar, a country with only 9% of the population ≥50 years old [8]. In contrast, a study analyzing data from 10 states of the United States of America found evidence of waning protection against hospitalization, with VE dropping from 91% at 2 months to 78% at 4 months of booster dose [7]. In addition to age, follow-up time seems essential in the analysis of waning. In a study performed in Finland only on individuals >70 years old, sustained protection was observed against admission to hospital and ICUs. Still, follow-up after booster was up to 2 months [9], which may at least partially explain the differences between their observed declines and what we found in VE in the elderly. Indeed, we observed the lowest VE against severity for the elderly past 4 months. Those previous studies provided no data about VE across age groups. Thus, differences in age groups and the follow-up time seem to be involved in the differences observed in VE after mRNA booster dose across the studies.

Assessment of vaccine waning from observational studies during the COVID-19 pandemic is methodologically challenging due to dynamic changes during the vaccination program. Challenges include prioritizing vaccine delivery to higher-risk groups, e.g., the elderly, individuals with comorbidities, and healthcare professionals, which led to more time after the booster dose than in other individuals. In addition, different intervals between the last dose in the primary vaccination series and the booster dose have been used in different places. All these factors are compounded by the different sublineages of the Omicron variant circulating during the follow-up period, which can introduce potential bias. However, conducting harmonized analyses in two countries at the national level mitigates the possibility of spurious results driven by unmeasured confounders.

Brazil and Scotland present several differences, such as variability in vaccination programs, circulating subvariants of Omicron, and population characteristics such as age structure, testing policy, and vaccination status. For example, up to April, Brazil had vaccinated less than 50% of the eligible population for booster doses, while in Scotland, this index was more than 85%. These aspects may have influenced the lower VE against infection in Brazil compared to Scotland. However, despite all dissimilarities between countries, a similar pattern of quickly VE waning against infection and durable protection against severe disease was observed, reinforcing the robustness of these findings.

To our knowledge, the present study is the largest to investigate the waning of mRNA booster doses against severe outcomes in the Omicron era. In both countries, similar results were obtained using different reference groups to assess vaccine protection: unvaccinated individuals in the main analysis and individuals with only two vaccine doses in the sensitivity analyses. We adjusted for several clinically relevant factors by deterministically linking various national clinical databases. Using a TND case–control study, we mitigated the risk of bias due to differences in health-seeking behavior between vaccinated and unvaccinated groups [14,28].

However, there are some limitations to note. First, we assumed all cases in the study period were associated with the Omicron variant. A few cases may have been due to other variants, including Delta. To mitigate this limitation, we restricted our analyses to the period when Omicron was dominant in both countries. Second, most of the tests performed in Brazil during the study period were lateral flow, which may induce bias in the results due to misclassifying cases as controls. Third, we were unable to discriminate between Omicron lineages in our study. Nevertheless, initial studies have suggested VE against Omicron subvariants to be similar [8,29,30]. Fourth, as in any observational study, residual confounding might exist. However, in previous studies, the adjustment for the chosen cofounders provided demonstrable control for bias. We cannot exclude that bias could arise from the unexpected effects of COVID-19 vaccines in other acute respiratory illnesses, protecting these individuals. Fifth, we have defined COVID-19-associated hospitalization as any admission episode that occurs within 14 days of a positive SARS-CoV-2 test or positive test within 72 hours of hospital admission. Consequently, a subset of hospitalizations may be composed of incidental cases. However, although possible in Scotland, such incidental cases are unlikely to occur in Brazil. The Brazilian hospitalization database used in the present study only includes individuals with severe acute respiratory syndrome symptoms tested for SARS-CoV-2 infection. Sixth, there are a disproportional number of individuals in our sample from Brazil’s first quintile of deprivation (low deprivation). It is likely due to the use of the municipality deprivation index, indicating that cities with lower deprivation maintain a broader testing policy than cities with higher deprivation. Seventh, asymptomatic and mild infections may have been underrecognized if previously infected individuals were not tested. In Brazil, we found negative VE against symptomatic infection in the younger group in the last period past booster. However, in the exploratory analysis using only individuals with previously confirmed SARS-CoV-2 infection, in this scenario, the result was not replicated, indicating a possible bias of under-ascertainment of previous infection in the younger individuals, with more unvaccinated individuals with previous undetected infection.

In summary, our study has shown that older individuals are at the highest risk of experiencing severe outcomes after infection with the Omicron variant, even after receiving a booster dose. The recommendation for a second mRNA booster dose, now being implemented for these groups in several countries, seems sensible for preventing severe forms of COVID-19. Our data indicate that infection prevention and, thus, community protection may not be a realistic target with currently available vaccines. The durability of protection against hospitalization and death remains an open question underscoring the need for studies with extended follow-up periods. New vaccines, mainly those aimed at interrupting transmission, possibly by enhancing mucosal immunity, are necessary to reduce the risk of Omicron infection and transmission.

Supporting information

S1 Appendix. Additional tables and figures.

Table A. Additional population characteristics. Table B. Conditions of QCovid risk algorithm. Table C. Vaccination status of individuals tested for SARS-CoV-2 in Brazil (A) and Scotland (B), according to the test result and severity of disease. Vaccinees data were detailed according to the time after each dose. Table D. Time interval in days—median (interquartile interval)—between vaccination and test in Brazil and Scotland, according to the type of vaccine used in the primary series. Table E. Vaccine effectiveness against symptomatic infection in Brazil and Scotland, expressed in percentages (95% CI), according to the type of vaccine used at the primary series and by age group. Reference group: individuals unvaccinated. Table F. Vaccine effectiveness against severe outcomes in Brazil and Scotland, expressed in percentages (95% CI), according to the type of vaccine used at the primary series and by age group. Reference group: individuals unvaccinated. Table G. Relative vaccine effectiveness against symptomatic infection in Brazil and Scotland expressed in percentages (95% CI) according to the type of vaccine used at the primary series and by age group. Reference group: individuals that received only a primary series. Table H. Relative vaccine effectiveness against severe disease in Brazil and Scotland expressed in percentages (95% CI) according to the type of vaccine used at the primary series and by age group. Reference group: individuals that received only a primary series. Table I. Vaccine effectiveness against symptomatic infection among individuals with a previously confirmed infection in Brazil compared to unvaccinated. Results were reported as percentages (95% CI), according to the type of vaccine used in the primary series and by age group. Fig A. Distribution of variants of concern in Brazil and Scotland over time. Brazil (A) and Scotland (B). Fig B. STROBE flowchart of the study population in Brazil (A) and Scotland (B). Fig C. Distribution case and control over time in each country for individuals unvaccinated or vaccinated with ChAdOx1 or BNT162b2 as primary series. Brazil (A) and Scotland (B). Fig D. Uptake of each dose, including booster dose, in individuals vaccinated with ChAdOx1 or BNT162b2 as primary series. Vaccination numbers in Brazil (A) and Scotland (B), stratified by age group and primary series. Different y-axis scales in each age group.

(DOCX)

Click here for additional data file. (713.7KB, docx)
S2 Appendix. STROBE/RECORD checklist.

(DOCX)

Click here for additional data file. (26.1KB, docx)
S3 Appendix. Statistical analysis plan.

(DOCX)

Click here for additional data file. (27.8KB, docx)

Acknowledgments

This study is part of the Fiocruz VigiVac program, and the authors acknowledge DATASUS for its diligent work in providing the unidentified Brazilian databases. GLW, MLB, VSB, and MB-N are Brazilian National Research Council research fellows. SVK acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). ESP acknowledges funding from the Wellcome Trust (213589/Z/18/Z). T.C.-S. is a PhD student at the Post-Graduation Program in Health Sciences-UFBA, which is supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil, finance code 001. We thank Dave Kelly from Albasoft (Inverness, UK) for his support with making primary care data available; Wendy Inglis-Humphrey, Vicky Hammersley, and Laura Brook (University of Edinburgh, Edinburgh, UK); and Pam McVeigh, Amanda Burridge, and Afshin Dastafshan (Public Health Scotland, Glasgow, UK) for their support with project management and administration.

Abbreviations

CI

confidence interval

COVID-19

Coronavirus Disease 2019

ICU

intensive care unit

OR

odds ratio

RT-PCR

reverse transcriptase polymerase chain reaction

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

TND

test-negative design

VE

vaccine effectiveness

VOC

variant of concern

Data Availability

Regarding Brazilian data availability, one of the study coordinators (M.B.-N.) signed a term of responsibility on using each database made available by the Ministry of Health (MoH). Each member of the research team signed a term of confidentiality before accessing the data. Data was manipulated in a secure computing environment, ensuring protection against data leakage. The Brazilian National Commission in Research Ethics approved the research protocol (CONEP approval no. 4.921.308). Our agreement with the MoH for accessing the databases patently denies authorization of access to a third party. Any information for assessing the databases must be addressed to the Brazilian MoH at https://datasus.saude.gov.br/, and requests can be addressed to datasus@saude.gov.br. In this study, we used anonymized secondary data following the Brazilian Personal Data Protection General Law, but it is vulnerable to re-identification by third parties as they contain dates of relevant health events regarding the same person. To protect the research participants’ privacy, the approved Research Protocol (CONEP approval no. 4.921.308) authorises the dissemination only of aggregated data, such as the data presented here. Regarding Scotland, the data that support the findings of this study are not publicly available because they are based on de-identified national clinical records. These are, however, available by application via Scotland’s National Safe Haven from Public Health Scotland. The data used in this study can be accessed by researchers through NHS Scotland’s Public Benefit and Privacy Panel via its Electronic Data Research and Innovation Service.

Funding Statement

The present study was suported by Fiocruz and partly supported by a donation from the "Fazer o Bem Faz Bem" programme from JBS S.A. MB-N received a grant from Fundação de Apoio do Estado da Bahia (FAPESB) – Grant PNX0008/2014/ Fapesb, Edital 08/2014 - Programa de Apoio a Núcleos de Excelência. GLW acknowledges Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/210.180/2020). This study is part of the EAVE II project. EAVE II is funded by the MRC (MC_PC_19075) (AS, SVK, CR) with the support of BREATHE—The Health Data Research Hub for Respiratory Health (MC_PC_19004) (AS), which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20058) (AS, SVK, CR). Additional support has been provided through Public Health Scotland and Scottish Government Director General Health and Social Care and National Core Studies - Immunology. The original EAVE project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (11/46/23) (AS). The Brazilian component is part of the Fiocruz VigiVac project on continuous digital evaluation of the national anti-COVID-19 immunization programme. SVK acknowledges funding from an NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02), the MRC (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). CR reports grants from the Medical Research Council (MRC) and Public Health Scotland during the conduct of the study. ESP is funded by the Wellcome Trust [Grant number 213589/Z/18/Z]. This partnership between Brazil and Scotland was established through funding from the NIHR (GHRG /16/137/99) using UK aid from the UK Government to support global health research(AS, SVK, CR, IR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Caitlin Moyer

19 May 2022

Dear Dr Cerqueira-Silva,

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Decision Letter 1

Caitlin Moyer

13 Jul 2022

Dear Dr. Cerqueira-Silva,

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We look forward to receiving your revised manuscript.

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Associate Editor

PLOS Medicine

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Requests from the editors:

From the Academic Editor:

The vaccine effectiveness literature is rapidly evolving. The benefits of a single booster are well characterised in the literature and the policy discussion now seems to be more focussed on whether a second booster should be provided to more populations (per WHO HCWs, elderly, and immunocompromised are already eligible for an additional booster, https://www.who.int/news/item/17-05-2022-interim-statement-on-the-use-of-additional-booster-doses-of-emergency-use-listed-mrna-vaccines-against-covid-19). Therefore, one suggestion was to see whether the authors can use their Brazilian and Scottish data to look at the impact of the fourth dose. Moreover, the primary vaccine series of ChAdOx1+mRNA booster is unique to specific countries and so I think teasing out the impact of this vaccine combination is worthwhile (currently they have combined it with primary mRNA vaccination series which can confound effects). Please find these suggestions below:

Major:

1. Existing literature (see Effectiveness of COVID-19 vaccines against SARS-CoV-2 variants of concern: a systematic review and meta-analysis. Zeng B, Gao L, Zhou Q, Yu K, Sun F. BMC Med. 2022 May 23;20(1):200) has shown that ChAdOx1 does not perform the same as BNT162b2. Due to potentially introducing confounding by primary vaccination series, please do not group these two together and compare primary vaccination series of BNT162b2+mRNA booster and primary vaccination series of ChAdOx1+mRNA booster with unvaccinated. On the same note in lines 292-307, please contextualise discussion of other studies by the primary vaccination series + booster in each country/study rather than exclusively grouping by number of vaccination doses.

2. The 13 week threshold used is unorthodox and inconsistent with other studies. As suggested by one of the reviewers, agree extending out to 6 months and evaluating greater than or equal to 6 months as the last waning threshold makes sense. If this is not possible at least use greater than or equal to 3 months (or 12 weeks).

3. Given the benefits of a fourth dose for specific populations (HCWs, elderly, immunocompromised (https://www.who.int/news/item/17-05-2022-interim-statement-on-the-use-of-additional-booster-doses-of-emergency-use-listed-mrna-vaccines-against-covid-19). Would suggest the authors consider updating the analysis to also include a second booster dose for whatever periods of follow-up and populations are available.

Minor:

4. The Qatari study has now been published and can be updated. Chemaitelly H, Ayoub HH, Al Mukdad S,et al. Duration of mRNA vaccine protection against SARS-CoV-2 Omicron BA.1 and BA.2 subvariants in Qatar. Nat Commun. 2022 Jun 2;13(1):3082.

5. In the limitations discussion sublineages can also add BA4 and BA 5 now.

Other Editorial Points:

6. Title: We suggest revising the title for clarification. Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. "Effect of" should be used only if causality can be inferred, i.e., for an RCT. Please place the study design ("A randomized controlled trial," "A retrospective study," "A modelling study," etc.) in the subtitle (ie, after a colon).

7. Data availability statement: Please provide the weblink/email contact information for requests to access the data from Scotland.

8. Abstract: Please structure your abstract using the three PLOS Medicine headings (Background, Methods and Findings, Conclusions). Please combine the Methods and Findings sections into one section, “Methods and findings”.

9. Abstract: Methods and Findings: Please describe the national databases, in terms of the populations represented and numbers of participants included, as well as the time period of the study, the maximum length of follow up, and how the main outcome measures were defined/quantified. We suggest including information similar to what is reported at lines 115-117 of the Methods (“All individuals aged 18 years or older who reported acute respiratory illness symptoms and tested for SARS-CoV-2 infection between January 1, 2022 and March 7, 2022 for Brazil and December 20, 2021 and March 9, 2022 for Scotland were eligible for the study”).

10. Abstract: Methods and Findings: Please report p values as p<0.001 where applicable.

11. Abstract: Methods and Findings: Please include a summary of adverse events if these were assessed in the study.

12. Abstract: Methods and Findings: In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

13. Abstract: Conclusions: Please address the study implications without overreaching what can be concluded from the data; the phrase "In this study, we observed ..." may be useful.

14. Author summary: At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

15. Main text: Please place in-text citations of references within brackets, before the sentence punctuation.

16. Methods: For all observational studies, in the manuscript text, please indicate: (1) the specific hypotheses you intended to test, (2) the analytical methods by which you planned to test them, (3) the analyses you actually performed, and (4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

17. Methods: Line 145: Please explain “comorbidities” and please describe all factors that were adjusted for, and explain how these data were obtained.

18. Methods: Line 151: Please describe QCovid risk group here.

19. Methods: Line 165-166: Please clarify if this refers to weeks: “A trend test, evaluating the change in estimate between 2-4, 5-8, 9-12, and ≥13 past booster dose…”

20. Methods: Statistical analyses: For analyses where a p value is given, please specify the statistical test used to determine it as well as the significance level used (eg, P<0.05, two-sided).

21. Methods: Please ensure that the study is reported according to the STROBE guideline. Thank you for including the completed STROBE checklist as Supporting Information.

Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

When completing the checklist, please use section and paragraph numbers throughout to indicate locations within the text.

22. Methods: Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

23. Results: Line 238-248: Please also provide p values for these results, where applicable.

24. Discussion: Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

25. Discussion: Line 267: Please clarify “severe Omicron COVID-19 outcomes” to indicate that this means Omicron era cases.

26. Figures and Tables: Please provide titles and legends for all figures (including those in Supporting Information files). Please check that any abbreviations used within Tables and Figures is completely defined in the legend. Please consider avoiding the use of red and green together in the same figure in order to make your figure more accessible to those with color blindness.

27. Figure 1 and Figure 2: Please indicate in the figure caption the meaning of the error bars. Please indicate in the legend if severe COVID-19 indicates both hospitalization and death.

28. S1 Table: Please describe in the Methods how characteristics of cases and controls were evaluated/reported. Please describe how characteristics (e.g. obesity/immunosuppression/respiratory disease/kidney disease/cardiac disease etc) were determined. How was race/ethnicity defined and by whom? In S1 part B, please use variable names under “characteristic” that are more intuitive and/or similar to S1 part A.

29. S2 Table: Please note all values are n(%).

30. S3 Table: Please include at the top that the categories represent ages. In Part B (Scotland, severe outcomes): In the legend please define cells with “*” indicated.

31. S4 Table, S5 Table: Where p values are reported, please report as p<0.001 where applicable. When p<0.01 please report to 3 decimal places, and when p>/=.01 please report to two decimal places. Please indicate that the table is presented by age category. In the legend, please define cells with “-” reported.

32. S6 Table: Please label the columns at the top with “age” and “primary series” as appropriate. In the legend for Part B, please define the cells with “*” reported.

33. S1 Appendix: There seems to be an unlabelled table between S6 Table and S7 Table, titled “Severe Outcomes” and reporting VE for each primary series type.

34. S7 Table: Part A: The right-hand side of the table is cut off.

Comments from the reviewers:

Reviewer #1: See attachment

Michael Dewey

Reviewer #2:

Review Cerqueira-Silva et al, PlosMed

The strength of this study is that it takes place in two countries, with different populations but similar vaccination strategies, among large populations. The design is solid and well-execulted. I have two high-level critiques. First, is that they call this a study of waning, even in the title, but only follow-up persons to 13+ weeks--- not sure exactly how long in that furthest follow-up group. This relatively short follow-up time is sufficient for symptomatic infection with omicron where waning happens swiftly, but probably not enough followup time for severe disease. 2. The authors overstate the amount of waning after booster among persons >=65 years. Their results show a minimal amount of decrease in VE (<10 percentage points) with overlapping CI< yet they lead off their discussion by highlighting the waning in this group.

Specific comments.

Line 94. Delete « offered »

Line 112. Lateral flow tests have lower sensitivity. Most tests in Brazil were lateral flow (Table 1) Authors could mention this as a potential limitation, due to misclassification of case status. Do they have test characteristics for the lateral flow tests used?

Line 142. What is vaccination coverage in general populations? If the unvaccinated percentage is small (<10%) it could suggest a potential bias among the remaining unvaccinated population in terms of their risk of exposure. From table 1, it seems that this is <10%, so this should be mentioned as a potential bias in the discussion (if not already).

Line 158. Given the matched enrollment in Scotland, how were the matched groups identified in the analysis. Why not conditional logistic regression?

Line 166. Missing "weeks"?

Line 170. Note that this sensitivity analysis will calculate a relative VE rather than an absolute VE. If there is still residual VE from two doses, then the relative Ve will be lower than absolute VE. More an issue for severe disease. it should be stated that this analysis yields a relative VE. This is seen in table S7 especially in Scotland.

Line 186. Replace word "and" with "compared with"??

Line 188. The median followup time since vaccination / booster should be given. In the >13 week group, what is the median folllowup time in that group. If it is not much more than 13 weeks, it is not very long.

Table 1. somewhat surprising that there are a greater percentage in the highest deprivation index categories in Scotland than Brazil. Why? Use of different deprivation indices?

Line 220, figures. The VE in Brazil was consistently higher, including by age group. Why do the authors think this is the case? They should comment on that. Although table 1 shows low prior infection in both countries, one wonders whether seroprevalence in the Brazilian population was higher, and most people didn't know, which would have lead to more hybrid immunity in that population.

Line 268. I don't think the data supports this statement that there is significant waning against severe disease in the >65 yo group. Figure 2 does show some drop in percentage point VE, but not lower than 80% and with overlapping confidence intervals. The authors state on line 227: modest waning from 89.5% (95%CI 88.0 - 90.8) at 2-4 weeks to 85.1% (95%CI 83.5 - 86.6) at 13 weeks or more. This is only 4 percentage points drop. this statement should be modified lest it be misinterpreted as these vaccines are not working in this high risk age group.

Line 293 and whole paragraph. Same comment about overstating of waning against severe disease in the elderly.

Line 315. There is no evidence that VE differs by BA1 and BA2 - data from UK, Qatar. No date on other omicron lineages. Probably not the same amount of difference in VE as with different variants in circulation.

Line 333. This does not seem to be the case for this vaccine. You could delete this limitation.

Instead I think a significant limitation to mention is the limited amount of time of followup post booster, which limits the assessment of waning.

Table S3. The negative VE >20 weeks after primary series in Scotland should be discussed. This is not a plausible finding and suggests a bias among those first vaccinated. Moreover, this seems more of an issue among the older age groups, and also evident to a lesser degree after booster. Most other studies that initially showed a negative VE found that it was no longer negative after adding more omicron cases. Scotland is an outlier in not having the strongly negative VE disappear.

Table S4. Trend test for what? Not clear.

Reviewer #3: This is a valuable and important paper that addresses clinical efficacy of mRNA vaccine boosting after mRNA or ChAdOx1 primary series vaccination. The comparison of two countries, with broadly comparable results, gives confidence.

Points

This is a comparison to unvaccinated subjects. The recommendation from the paper is that booster vaccination should be promoted. How do the findings compare to people who have primary series vaccination but no booster ?

Table 1 shows that the demographics of the case positive and use negative groups are somewhat dissimilar. Have these been assessed for statistical difference and could this influence the analysis.

Considerable emphasis is given to waning in subjects >65 years in Brazil whereas the values are not markedly dissimilar from the total cohort. Is there any reason why this was picked out ?

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachment

Submitted filename: cerqueirasilva.pdf

Click here for additional data file. (59KB, pdf)

Decision Letter 2

Philippa Dodd

21 Oct 2022

Dear Dr. Cerqueira-Silva,

Thank you very much for submitting your manuscript "Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland:  a test-negative design case-control study" (PMEDICINE-D-22-01640R2) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by Nov 04 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Pippa

Philippa Dodd MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

GENERAL

Thank you for addressing previous reviewer and editor comments

Please address all editor and reviewer comments detailed below and in the attached file

DATA AVAILBILITY STATEMENT

Thank you for updating your data availability statement. Please also include this in your manuscript submission form – the older statement is still placed here – and remove from the end of the manuscript.

ABSTRACT

Please quantify main results with p-values as well as 95% CIs (this is currently a journal requirement)

When p<0.01 please report to 3 decimal places, and when p>/=.01 please report to 2 decimal places

Thank you for adding a limitation of your study – are there any others? Such as follow-up time post booster, inability to discriminate between omicron lineages etc. Please include all the primary limitations.

Where you report statistical results, please add a space between % symbols and CI i.e. line 55: “(95%CI…”. This is repeated throughout, please check and amend.

AUTHOR SUMMARY

Thank you for including an author summary. Please ensure it is structured according to PLOS Medicine’s style as described here: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary Specifically, please note the requirement for individually bulleted points and the requirement for the summary to be distinct from the abstract and accessible to the general reader.

METHODS and RESULTS

Please quantify main results with p-values as well as 95% CIs (this is currently a journal requirement)

Where p values are reported please also specify the statistical test used to determine it as well as the significance level used (eg p <0.05 two sided)

Line 140: “…for Brazil and Scotland” suggest “in” instead of “for” please revise

Line 177: “QCovid risk groups are…” I think it would be helpful to define the QCovid risk before you mention it. As written, it appears as though it is an after-thought and actually, it is vital for the reader to understand how the impact of co-morbidity in this group was accounted for.

It might also be helpful to include the QCovid risk algorithm that you utilized in your analyses in the supporting files – I understand that you have made reference to it but, if possible, it would be helpful to the reader to include it.

Line 206: “This study is reported following Strengthening….” Please place this statement at the beginning of the methods section

Line 209: “The original statistical plan is provided as supplementary appendix.” Suggest “prospective” instead of “original” – please revise throughout because as written, this statement implies that there is a revised analysis plan. Please move this sentence to the beginning of the section entitled “Statistical analysis” Please also indicate where in the appendix this information can be found i.e. S3 as per your manuscript.

In response to point 28 from the previous revision you state the following: “A: All data used in our analysis came from structured administrative databases. No detailed information about the definition of the characteristics was provided.” Please ensure that a relevant sentence is included in your methods section and indicate where you have placed it

FIGURES & TABLES

Thank you for including appropriate captions for Figure 1 and Figure 2. In both, instead of “line” suggest “error bars represent 95% Wald confidence interval.”

Please also include table captions, including for those in the supporting information, which clearly describe the content and include any abbreviations

Please define the numerical values, i.e. n (%), in table column headings (as you have [partially] done for table 1) as opposed to as a footnote – perhaps in the control column?

Table 1 – please remove “N(%)” from the end of the table and include the (%) in the column headings

In all tables where you report 95% CIs please also report p-values – to conserve space and/or the need for splitting your tables, which are already very full with data, I would consider detailing the p-value significance level in the relevant caption and placing asterisks adjacent to the CIs to reflect the result.

In the table captions please also report the statistical tests used to determine the p-value

Table S2: foot note reads “n (row percent%)” which is confusing to me, please revise for clarity and place this information in column headings (see above)

Table S4 – S8: all titles state the following “Vaccine Effectiveness % (95% CI) against…” suggest for clarity: “ Vaccine Effectiveness reported as percentages (95% CI) against…” or something similar

Figure 1, figure 2, figure S3B and figure S4: Please confirm that this shade of green is selected from a colour palate that this is accessible to those with color blindness – it appears to be a different shade from that used in figure S3A, at least on my monitor!

Figure S2B: the test is very small and rather inaccessible to the reader, please revise

Please remove the data availability statement from the end of the manuscript and please remove the conflict-of-interest statement from the end of the manuscript. This information should be included in the manuscript submission form only and will be complied as metadata

REFERENCES

For in-text reference callouts please add a space between the text and the first of the parentheses. For example line 99: “…wane over time[4,5], prompting…” should read: “…wane over time [4,5], prompting…”. This error is repeated throughout, please check thoroughly and amend

SOCIAL MEDIA

To help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.

Comments from the reviewers:

Reviewer #1: See attachment

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Attachment

Submitted filename: cerqueirasilva.pdf

Click here for additional data file. (56.9KB, pdf)

Decision Letter 3

Philippa Dodd

9 Dec 2022

Dear Dr. Cerqueira-Silva,

Thank you very much for re-submitting your manuscript "Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland:  a test-negative design case-control study" (PMEDICINE-D-22-01640R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by the methodological reviewer. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Dec 16 2022 11:59PM.   

Sincerely,

Philippa Dodd, MBBS MRCP PhD

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

GENERAL

Thank you for your considerate and detailed responses to previous editor and reviewer requests which we believe have substantially improved your manuscript.

In parts the manuscript reads somewhat as though it has been written by two individuals. This is probably, and understandably, the case given the nature of the study design but it would be beneficial to improve the uniformity of the writing style.

Please respond to all comments detailed below, in full.

We note the reviewer comments regarding the use of two data sets. The editorial team has discussed this point and have split opinions. The academic editor notes a precedent for the use of two data sets in similar studies and the other reviewers think that the inclusion of the two data sets offer an advance, therefore we conclude that it perhaps amounts to a difference of opinion.

COMMENTS FROM THE ACADEMIC EDITOR

There is precedent for including multiple datasets in the same manuscript. I've seen it done to compare heterogeneous settings for HIV treatment outcomes. Here the vaccines administered, and SARS-CoV-2 transmission levels, are different across Scotland and Brazil so the comparisons can be useful.

CONFLICT OF INTEREST STATEMENT

Author Aziz Sheikh sits on the PLOS Medicine Editorial Board. Please add this statement to the manuscript's Competing Interests: "AS is an Academic Editor on PLOS Medicine's editorial board." I could not see that it had been listed.

ABSTRACT

We asked the following: “Thank you for adding a limitation of your study – are there any others? Such as follow up time post booster, inability to discriminate between omicron lineages etc. Please include all the primary limitations” but could not see any amendments, please revise accordingly.

Line 57 statistical reporting: “37.4% (95% CI 33.8 – 40.9; p<0.001)” thank you for including p-values and CIs suggest reporting as follows “37.4% (95% CI [33.8, 40.9], p<0.001). Please check and amend throughout the abstract, author summary and main manuscript to ensure consistency of reporting

AUTHOR SUMMARY

Line 82: as above, “(from 51.6% [95% confidence interval:CI - 51.0 – 52.2] to 4.2% [95% CI 0.7 – 7.6])” your statistical reporting is rather difficult to interpret, and the use of multiple hyphens can lead to confusion between negative values and intervals.

Suggest the following: “from 51.6%, 95% confidence interval (CI): [51.0, 52.2], to 4.2% [95% CI: 0.7, 7.6])” . Note the absence of the first set of parentheses. Please check and revise throughout

Please include p-values where you report 95% CIs

Line 84: sentence beginning “In these periods…” suggest make a separate bulleted for this statement

Line 93: “Similar findings in two very distinct countries allow us to draw reliable results because each country has different key sources of potential bias unrelated to each other”

It would be helpful to clarify “potential bias unrelated to each other”, this statement is vague and unclear to the general reader. In addition, formal comparisons between the two data sets were not made so this statement can’t be fully substantiated by the dataset presented.

I would perhaps reword this statement and consider removing it from the conclusions to the previous section “what did the researchers do and find” as it seems partly aimed at justifying the use of the two data sets.

METHODS and RESULTS

Please amend statistical reporting as described above

TABLES

Table S2: please define numerical values within and outside of parentheses – suggest “n (%)” as in other tables

FIGURES

Figure S2 B) – please define TND and RT PCR in an appropriate caption

SOCIAL MEDIA

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Comments from Reviewers:

Reviewer #1: The authors have addressed my points. I still do not see what the added value of having two cohorts presented together is but I seem to be alone in my confusion.

Michael Dewey

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 4

Philippa Dodd

13 Dec 2022

Dear Dr Cerqueira-Silva, 

On behalf of my colleagues and the Academic Editor, Dr. Amitabh Suthar, I am pleased to inform you that we have agreed to publish your manuscript "Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland:  a test-negative design case-control study" (PMEDICINE-D-22-01640R4) in PLOS Medicine.

Please note this final amendment in the abstract methods and findings section at line 10:

“…booster was 51.6%, 95% confidence interval (CI): ([ 51.0, 52.2], p<0.001) in Brazil…” should read: “booster was 51.6%, (95% confidence interval (CI): [51.0, 52.2], p<0.001) in Brazil” note the alteration to the placement of circular parentheses. Please amend prior to publication.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

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Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Philippa Dodd, MBBS MRCP PhD 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix. Additional tables and figures.

    Table A. Additional population characteristics. Table B. Conditions of QCovid risk algorithm. Table C. Vaccination status of individuals tested for SARS-CoV-2 in Brazil (A) and Scotland (B), according to the test result and severity of disease. Vaccinees data were detailed according to the time after each dose. Table D. Time interval in days—median (interquartile interval)—between vaccination and test in Brazil and Scotland, according to the type of vaccine used in the primary series. Table E. Vaccine effectiveness against symptomatic infection in Brazil and Scotland, expressed in percentages (95% CI), according to the type of vaccine used at the primary series and by age group. Reference group: individuals unvaccinated. Table F. Vaccine effectiveness against severe outcomes in Brazil and Scotland, expressed in percentages (95% CI), according to the type of vaccine used at the primary series and by age group. Reference group: individuals unvaccinated. Table G. Relative vaccine effectiveness against symptomatic infection in Brazil and Scotland expressed in percentages (95% CI) according to the type of vaccine used at the primary series and by age group. Reference group: individuals that received only a primary series. Table H. Relative vaccine effectiveness against severe disease in Brazil and Scotland expressed in percentages (95% CI) according to the type of vaccine used at the primary series and by age group. Reference group: individuals that received only a primary series. Table I. Vaccine effectiveness against symptomatic infection among individuals with a previously confirmed infection in Brazil compared to unvaccinated. Results were reported as percentages (95% CI), according to the type of vaccine used in the primary series and by age group. Fig A. Distribution of variants of concern in Brazil and Scotland over time. Brazil (A) and Scotland (B). Fig B. STROBE flowchart of the study population in Brazil (A) and Scotland (B). Fig C. Distribution case and control over time in each country for individuals unvaccinated or vaccinated with ChAdOx1 or BNT162b2 as primary series. Brazil (A) and Scotland (B). Fig D. Uptake of each dose, including booster dose, in individuals vaccinated with ChAdOx1 or BNT162b2 as primary series. Vaccination numbers in Brazil (A) and Scotland (B), stratified by age group and primary series. Different y-axis scales in each age group.

    (DOCX)

    Click here for additional data file. (713.7KB, docx)
    S2 Appendix. STROBE/RECORD checklist.

    (DOCX)

    Click here for additional data file. (26.1KB, docx)
    S3 Appendix. Statistical analysis plan.

    (DOCX)

    Click here for additional data file. (27.8KB, docx)
    Attachment

    Submitted filename: cerqueirasilva.pdf

    Click here for additional data file. (59KB, pdf)
    Attachment

    Submitted filename: Response Letter.docx

    Click here for additional data file. (41.7KB, docx)
    Attachment

    Submitted filename: cerqueirasilva.pdf

    Click here for additional data file. (56.9KB, pdf)
    Attachment

    Submitted filename: Revision 2 - PMED.docx

    Click here for additional data file. (22.9KB, docx)
    Attachment

    Submitted filename: Requests from Editors_plos.docx

    Click here for additional data file. (17.4KB, docx)

    Data Availability Statement

    Regarding Brazilian data availability, one of the study coordinators (M.B.-N.) signed a term of responsibility on using each database made available by the Ministry of Health (MoH). Each member of the research team signed a term of confidentiality before accessing the data. Data was manipulated in a secure computing environment, ensuring protection against data leakage. The Brazilian National Commission in Research Ethics approved the research protocol (CONEP approval no. 4.921.308). Our agreement with the MoH for accessing the databases patently denies authorization of access to a third party. Any information for assessing the databases must be addressed to the Brazilian MoH at https://datasus.saude.gov.br/, and requests can be addressed to datasus@saude.gov.br. In this study, we used anonymized secondary data following the Brazilian Personal Data Protection General Law, but it is vulnerable to re-identification by third parties as they contain dates of relevant health events regarding the same person. To protect the research participants’ privacy, the approved Research Protocol (CONEP approval no. 4.921.308) authorises the dissemination only of aggregated data, such as the data presented here. Regarding Scotland, the data that support the findings of this study are not publicly available because they are based on de-identified national clinical records. These are, however, available by application via Scotland’s National Safe Haven from Public Health Scotland. The data used in this study can be accessed by researchers through NHS Scotland’s Public Benefit and Privacy Panel via its Electronic Data Research and Innovation Service.

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