key: cord-0267857-duflh7xo authors: Abu-Raddad, L. J.; Chemaitelly, H.; Ayoub, H. H.; YASSINE, H. M.; Benslimane, F.; Al Khatib, H. A.; Tang, P.; Hasan, M. R.; Coyle, P.; Al Kanaani, Z.; Al Kuwari, E.; Jeremijenko, A.; Kaleeckal, A. H.; Latif, A. N.; Shaik, R. M.; Abdul Rahim, H. F.; Nasrallah, G.; Al Kuwari, M. G.; Butt, A. A.; Al Romaihi, H. E.; Al-Thani, M. H.; Al Khal, A.; Bertollini, R. title: Waning of mRNA-1273 vaccine effectiveness against SARS-CoV-2 infection in Qatar date: 2021-12-16 journal: nan DOI: 10.1101/2021.12.16.21267902 sha: 18b085703a564b552aa399017aca120eebae1ab3 doc_id: 267857 cord_uid: duflh7xo BACKGROUND: In early 2021, Qatar launched a mass immunization campaign with Moderna mRNA-1273 COVID-19 vaccine. We assessed persistence of real-world mRNA-1273 effectiveness against SARS-CoV-2 infection and against COVID-19 hospitalization and death. METHODS: Effectiveness was estimated using test-negative, case-control study design, between January 1 and December 5, 2021. Effectiveness was estimated against documented infection (a PCR-positive swab, regardless symptoms), and against any severe (acute-care hospitalization), critical (ICU hospitalization), or fatal COVID-19. RESULTS: By December 5, 2021, 2,962 breakthrough infections had been recorded among those who received two mRNA-1273 doses. Of these infections, 19 progressed to severe COVID-19 and 4 to critical, but none to fatal disease. mRNA-1273 effectiveness against infection was negligible for the first two weeks after the first dose, increased to 65.5% (95% CI: 62.7-68.0%) 14 or more days after the first dose, and reached its peak at about 90% in the first three months after the second dose. Effectiveness declined gradually starting from the fourth month after the second dose and was below 50% by the 7th month after the second dose. Effectiveness against severe, critical, or fatal COVID-19 reached its peak at essentially 100% right after the second dose, and there was no evidence for declining effectiveness over time. Effectiveness against symptomatic versus asymptomatic infection demonstrated the same pattern of waning, but effectiveness against symptomatic infection was consistently higher than that against asymptomatic infection and waned more slowly. CONCLUSIONS: mRNA-1273-induced protection against infection appears to wane month by month after the second dose. Meanwhile, protection against hospitalization and death appears robust with no evidence for waning for several months after the second dose. Vaccine effectiveness was estimated using the test-negative, case-control study design, a standard design for assessing vaccine effectiveness. 2, [9] [10] [11] [12] [13] [14] [15] [16] Cases (PCR-positive persons) and controls (PCR-negative persons) were matched one-to-two by sex, 10-year age group, nationality, reason for SARS-CoV-2 PCR testing, and calendar week of PCR testing to estimate vaccine effectiveness against SARS-CoV-2 infection; and one-to-five to estimate vaccine effectiveness against any severe, critical, or fatal COVID-19 (to improve statistical precision given the relatively small number of severe forms of . Matching was performed to control for known differences in the risk of exposure to SARS-CoV-2 infection in Qatar. 8, [17] [18] [19] [20] Only the first PCR-positive test during the study was included for each case, and only the first PCR-negative test during the study was included for each control. PCR tests done for pre-travel or at the port of entry were excluded from analysis. All PCR-negative tests for persons included as cases were excluded from analysis. These inclusion and exclusion criteria were implemented to minimize different types of potential bias, as informed by prior analyses. 3 All persons who received mixed vaccines, or who received a vaccine other than mRNA-1273, or who were tested by PCR after receiving a booster dose were excluded. Every case that met the inclusion criteria and that could be matched to a control was included in the analysis. Both PCRtest outcomes and vaccination status were ascertained at the time of the PCR test. Effectiveness was estimated against documented infection (defined as a PCR-positive swab, regardless of the reason for PCR testing or the presence of symptoms), as well as against any severe, 21 critical, 21 or fatal 22 COVID-19. Classification of COVID-19 case severity (acute-care hospitalizations), 21 criticality (ICU hospitalizations), 21 and fatality 22 followed World Health Organization (WHO) guidelines, and assessments were made by trained medical personnel using individual chart reviews (Section S1). Each person who had a positive PCR test result and hospital admission was subject to an infection severity assessment every three days until discharge or death, regardless of the length of the hospital stay or the time between the PCR-positive test and the final disease outcome. Individuals who progressed to severe, 21 critical, 21 or fatal 22 COVID-19 between the PCR-positive test result and the end of the study were classified based on their worst outcome, starting with death, followed by critical disease, and then severe disease. Details of laboratory methods for real-time reverse-transcription PCR (RT-qPCR) testing are found in Section S2. All PCR testing was conducted at the Hamad Medical Corporation Central Laboratory or at Sidra Medicine Laboratory, following standardized protocols. Institutional Review Boards with a waiver of informed consent. Reporting of the study followed STROBE guidelines (Table S1 ). All records of PCR testing in Qatar during the study were included, but only samples of matched cases and controls were included in the analysis. Demographic characteristics of study samples were described using frequency distributions and measures of central tendency. The odds ratio, comparing odds of vaccination among cases versus controls, and its associated 95% confidence interval (CI) were derived using conditional logistic regression, that is factoring the matching in the study design. This matching and analysis approach aims to minimize potential bias due to variation in epidemic phase, 9, 23 gradual roll-out of vaccination during the study, 9, 23 or other confounders. 24,25 CIs were not adjusted for multiplicity. Interactions were not investigated. Vaccine effectiveness at different time points and its associated 95% CI were then calculated by applying the following equation. 9, 10 odds ratio of vaccination among cases versus controls Vaccine effectiveness 1 =− . In each analysis for a specific time-since-vaccination stratum, we included only those vaccinated in that specific time-since-vaccination stratum and those unvaccinated (our reference group). Only matched pairs of PCR-positive and PCR-negative persons, in which members of the pair were either unvaccinated or fell within each time-since-vaccination stratum were included in the All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Between January 1 and December 5, 2021, 893,779 individuals received at least one mRNA-1273 dose and 887,726 completed the two-dose regimen. The median date for the first dose was May 27, 2021, and that for the second dose was June 27, 2021. The median time elapsed between the two doses was 28 days (interquartile range, 28-30 days). By December 5, 2021, 2,962 breakthrough infections had been recorded among those who received two doses. Of these infections, 19 progressed to severe COVID-19 and 4 to critical, but none to fatal disease. Figure 1 depicts the process used to select the study population. Tables 1-3 show the characteristics of samples used in the analysis. Only ~35% of cases were diagnosed because of symptoms. The remaining cases were diagnosed because of PCR testing for contact tracing, surveys or random testing campaigns, individual requests, and routine healthcare testing. mRNA-1273 effectiveness against infection was negligible for the first two weeks after the first dose, increased to 65.5% (95% CI: 62.7-68.0%) 14 or more days after the first dose, and reached its peak at about 90% in the first three months after the second dose ( Figure 2 and Table 4 ). Effectiveness declined gradually starting from the fourth month after the second dose and was below 50% by the 7 th month after the second dose. Effectiveness against severe, critical, or fatal COVID-19 reached its peak at essentially 100% right after the second dose, and there was no evidence for declining effectiveness over time. Sensitivity analysis that adjusted for prior infection and healthcare worker status showed same pattern of waning (Table 5) . Effectiveness for those <50 years of age and those ≥50 were similar in absolute value and showed the same pattern of waning (Table 6 ). Effectiveness against symptomatic versus asymptomatic infection demonstrated the same pattern of waning, but effectiveness against symptomatic infection was consistently higher than that against asymptomatic infection and All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 waned more slowly ( Figure 2 and Table 7 ). The above measures largely reflected effectiveness against the Beta and Delta variants that dominated incidence during the study. [3] [4] [5] Discussion mRNA-1273-induced protection against infection appears to wane month by month after the second dose. Meanwhile, protection against hospitalization and death appears robust with no evidence for waning for several months after the second dose. Since the immunization campaign prioritized vaccination of persons with severe or multiple chronic conditions and by age group, the observed pattern of waning of protection could theoretically be confounded by effects of age and comorbidities. Individual-level data on comorbid conditions were not available; therefore, they could not be explicitly factored into our analysis. However, only a small proportion of the study population may have had serious comorbid conditions. Only 9% of the population of Qatar are ≥50 years of age, 7,8 and 60% are young, expatriate craft and manual workers working in mega-development projects. 19, 20, 26 The national list of persons prioritized to receive the vaccine during the first phase of vaccine roll-out included only 19,800 individuals of all age groups with serious co-morbid conditions. Old age may serve as a partial proxy for co-morbid conditions. A similar pattern of waning of protection was observed for younger and older persons (Table 6) . Notably, with the small proportion of Qatar's population being ≥60 years of age, 7,8 our findings may not be generalizable to other countries in which elderly citizens constitute a larger proportion of the total population. Infection incidence was dominated sequentially by different variants; [2] [3] [4] [5] 14, 27, 28 thus, it is possible that waning of protection could be confounded by exposure to different variants at different times. However, this seems unlikely, as a similar pattern of waning was observed in our recent All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 study of the BNT162b2 vaccine for the Alpha, 29 Beta, 29 and Delta 29 variants in the same population. 3 Vaccinated persons presumably have a higher social contact rate than unvaccinated persons, and they may also adhere less strictly to safety measures. [30] [31] [32] This behavior could reduce real-world effectiveness of the vaccine compared to its biological effectiveness, possibly explaining the waning of protection. Public health restrictions have been easing gradually in Qatar, but differently for vaccinated and unvaccinated persons. Many social, work, and travel activities presently require evidence of vaccination (a "health pass") that is administered through a mandatory mobile app (the Ehteraz app). However, risk compensation is perhaps more likely to affect the overall estimate of effectiveness, rather than the observed waning of protection over time, unless such risk compensation increases with time after the second dose. PCR testing in Qatar is done on a mass scale, such that about 5% of the population are tested every week. 3 About 75% of those diagnosed at present are diagnosed not because of symptoms, but because of routine testing. 3 It is possible that many asymptomatic infections were diagnosed among vaccinated persons that otherwise would have been missed. The higher ascertainment of infection may have reduced the effectiveness estimates. This is supported by the observed lower effectiveness against asymptomatic infection (Table 7) . Effectiveness was assessed using an observational, test-negative, case-control study design, 9, 10 rather than a randomized, clinical trial design, in which cohorts of vaccinated and unvaccinated individuals were followed up. We were unable to use a cohort study design due to depletion of unvaccinated cohorts by the high vaccine coverage. However, the cohort study design applied earlier to the same population of Qatar yielded findings similar to those of the test-negative casecontrol design, 2,14-16 supporting the validity of this standard approach in assessing vaccine All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 effectiveness for respiratory tract infections. 2, [9] [10] [11] [12] [13] [14] [15] [16] The results of this study are also consistent with our earlier effectiveness estimates immediately after the first and second doses, 2, 16 noting that estimated measures largely reflected effectiveness against the Beta and Delta variants that dominated incidence during that study. [2] [3] [4] [5] 14, 27, 28 To rapidly scale up vaccination, some vaccination campaigns are conducted outside healthcare facilities; thus, records of vaccination are not immediately uploaded into the CERNER system, which tracks all vaccination records at the national level. This administrative time delay can introduce a misclassification bias of those vaccinated versus those unvaccinated. A sensitivity analysis investigating the impact of such potential bias, by assuming a 10% misclassification bias of those vaccinated and unvaccinated in Table 4 , found very limited difference in estimated effectiveness. A key strength of the test-negative, case-control study design is that it is less susceptible to this form of bias. 9, 10 Nonetheless, one cannot exclude the possibility that in real-world data, bias could arise in unexpected ways, or from unknown sources, such as subtle differences in test-seeking behavior or changes in the pattern of testing with introduction of other testing modalities, such as rapid antigen testing. Notwithstanding these limitations, consistent findings were reached, indicating a large effect size for the waning of vaccine protection over time, regardless of the reason for PCR testing, and regardless of the presence or absence of symptoms. Moreover, with the mass scale of PCR testing in Qatar, 3 the likelihood of bias is perhaps minimized. Extensive sensitivity and additional analyses were conducted to investigate effects of potential bias in our recent study for the BNT162b2 vaccine, 3 which used the same methodology as the present study. All analyses presented consistent findings of waning vaccine protection. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. well as for support provided by the Ministry of Public Health, Hamad Medical Corporation, and Sidra Medicine. The authors are also grateful for the Qatar Genome Programme and Qatar University Biomedical Research Center for institutional support for the reagents needed for the viral genome sequencing. Statements made herein are solely the responsibility of the authors. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the article. LJA conceived and co-designed the study, led the statistical analyses, and co-wrote the first draft of the article. HC co-designed the study, performed the statistical analyses, and co-wrote the first draft of the article. PT and MRH conducted the multiplex, RT-qPCR variant screening and viral genome sequencing. HY, FMB, and HAK conducted viral genome sequencing. All authors contributed to data collection and acquisition, database development, discussion and interpretation of the results, and to the writing of the manuscript. All authors have read and approved the final manuscript. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org /10.1101 /10. /2021 Dr. Butt has received institutional grant funding from Gilead Sciences unrelated to the work presented in this paper. Otherwise we declare no competing interests. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Table 2 . Demographic characteristics of subjects and reasons for PCR testing among samples used to estimate mRNA-1273 vaccine effectiveness. The table includes samples used in the 2 nd -month-after-second-dose analysis, 3 rd -month-after-seconddose analysis, and 4 th -month-after-second-dose analysis. Table 3 . Demographic characteristics of subjects and reasons for PCR testing among samples used to estimate mRNA-1273 vaccine effectiveness. The table includes samples used in the 5th-month-after-second-dose analysis, 6th-month-after-seconddose analysis, 7th-month-after-second-dose, and 8th-month-after-second-dose analysis. Characteristics 5 th -month-after-second-dose 6 th -month-after-second-dose 7 th -month-after-second-dose 8 th -month-after-second-dose Cases * (PCRpositive) All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Supplementary Appendix Table of All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Section S2. Laboratory methods Nasopharyngeal and/or oropharyngeal swabs were collected for PCR testing and placed in Universal Transport Medium (UTM). Aliquots of UTM were: extracted on a QIAsymphony platform (QIAGEN, USA) and tested with real-time reverse-transcription PCR (RT-qPCR) using TaqPath COVID-19 Combo Kits (Thermo Fisher Scientific, USA) on an ABI 7500 FAST (Thermo Fisher, USA); tested directly on the Cepheid GeneXpert system using the Xpert Xpress SARS-CoV-2 (Cepheid, USA); or loaded directly into a Roche cobas 6800 system and assayed with a cobas SARS-CoV-2 Test (Roche, Switzerland). The first assay targets the viral S, N, and ORF1ab gene regions. The second targets the viral N and E-gene regions, and the third targets the ORF1ab and E-gene regions. All PCR testing was conducted at the Hamad Medical Corporation Central Laboratory or Sidra Medicine Laboratory, following standardized protocols. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Tables 1-3 (b) Indicate number of participants with missing data for each variable of interest NA, see Methods ('Study population, data sources, and study design') Outcome data 15 Report numbers in each exposure category, or summary measures of exposure Results, Figure 2 , & Tables 4-5 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included Results, Figure 2 , & Tables 4-5 (b) Report category boundaries when continuous variables were categorized Tables 1-3 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period NA Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses Results & Tables 6-7 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted December 16, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar Infection With Risk of Breakthrough Infection Following mRNA Vaccination in Qatar Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Characterizing the Qatar advancedphase SARS-CoV-2 epidemic The test-negative design for estimating influenza vaccine effectiveness Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness Effectiveness of COVID-19 vaccines against variants of concern Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant SARS-CoV-2 vaccine effectiveness in preventing confirmed infection in pregnant women BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar Mathematical modeling of the SARS-CoV-2 epidemic in Qatar and its impact on the national response to COVID-19 ) 31,284 (21.0) 18,146 (20.7) 31,186 (21.0) 30-39 years 2) 42,010 (27.8) 23,876 (27.1) 41,418 (27.8) 23,665 (27.0) 41,262 (27.8) Nepalese PCR, polymerase chain reaction SMD, standardized mean difference. * Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test. † Nationalities were chosen to represent the most populous groups in Qatar 102 other nationalities in the ≥14-days-after-first-dose-and-no-second-dose analysis, and 102 other nationalities in the 1st-month-aftersecond-dose analysis. 051 (20.8) 30,884 (21.0) 18,023 (20.7) 30,861 (21.0) 18,032 (20.7) 30,869 (21.0) 30-39 years 26,976 (31.0) 45,264 (30.8) 26,979 (31.0) 45,178 (30.8) 27,013 (31.1) 45,213 (30.8) 40-49 years Abbreviations: IQR, interquartile range; PCR, polymerase chain reaction. * Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test. † Nationalities were chosen to represent the most populous groups in Qatar 20.7) 30,720 (21.0) 30-39 years 26,990 (31.0) 45,138 (30.7) 26,924 (31.0) 45,030 (30.7) 26,965 (31.1) 45,085 (30.8) 4) Healthcare routine testing 10 Abbreviations: IQR, interquartile range; PCR, polymerase chain reaction. * Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test. † Nationalities were chosen to represent the most populous groups in Qatar ‡ These comprise 102 other nationalities in Qatar in the 5th-month-after-second-dose analysis, 102 other nationalities in the 6th-month-after-second-dose analysis, 102 other nationalities in the 7th-month-after-second-dose analysis, and 102 other nationalities in the 8th-month-after-second-dose analysis COVID-19 severity, criticality, and fatality classification Severe Coronavirus Disease 2019 (COVID-19sentences, and, in children, very severe chest wall indrawing, grunting All rights reserved. No reuse allowed without permission the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. References 1. World Health Organization. COVID-19 clinical management: living guidance We acknowledge the many dedicated individuals at Hamad Medical Corporation, the Ministry of Public Health, the Primary Health Care Corporation, the Qatar Biobank, Sidra Medicine, and Weill Cornell Medicine -Qatar for their diligent efforts and contributions to make this study possible.The authors are grateful for support from the Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, both at Weill Cornell Medicine-Qatar, as 19 ¶ SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. -194.4 to 100.0) ¶ Abbreviations: CI, confidence interval; PCR, polymerase chain reaction. * In each analysis for a specific time-since-vaccination stratum, we included only those vaccinated in this specific time-since-vaccination stratum and those unvaccinated. Only matched pairs of PCR-positive and PCR-negative persons, in which both members of the pair were either unvaccinated or fell within each time-since-vaccination stratum have been included in the corresponding vaccine effectiveness estimate. Thus, the number of cases (and controls) varied across time-since-vaccination analyses. † Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test in analysis of effectiveness against infection, and one-to-five in analysis of effectiveness against hospitalization and death. ‡ Vaccine effectiveness was estimated using the test-negative, case-control study design. 9,10 § Severity, 21 criticality, 21 and fatality 22 were defined as per World Health Organization guidelines. ¶ Confidence interval could not be estimated using conditional logistic regression because of zero events among those vaccinated. Alternatively, the confidence interval was estimated using the standard error of the crude odds ratio after adding 0.5 to each of the number of vaccinated cases and number of unvaccinated cases. -194.4 to 100.0) ¶ Abbreviations: CI, confidence interval; PCR, polymerase chain reaction. * In each analysis for a specific time-since-vaccination stratum, we included only those vaccinated in this specific time-since-vaccination stratum and those unvaccinated. Only matched pairs of PCR-positive and PCR-negative persons, in which both members of the pair were either unvaccinated or fell within each time-since-vaccination stratum have been included in the corresponding vaccine effectiveness estimate. Thus, the number of cases (and controls) varied across time-since-vaccination analyses. † Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test in analysis of effectiveness against infection, and one-to-five in analysis of effectiveness against hospitalization and death. ‡ Vaccine effectiveness was estimated using the test-negative, case-control study design. 9,10 § Severity, 21 criticality, 21 and fatality 22 were defined as per World Health Organization guidelines. ¶ Confidence interval could not be estimated using conditional logistic regression because of zero events among those vaccinated. Alternatively, the confidence interval was estimated using the standard error of the crude odds ratio after adding 0.5 to each of the number of vaccinated cases and number of unvaccinated cases. Abbreviations: CI, confidence interval; PCR, polymerase chain reaction. * In each analysis for a specific time-since-vaccination stratum, we included only those vaccinated in this specific time-since-vaccination stratum and those unvaccinated. Only matched pairs of PCR-positive and PCR-negative persons, in which both members of the pair were either unvaccinated or fell within each time-since-vaccination stratum have been included in the corresponding vaccine effectiveness estimate. Thus, the number of cases (and controls) varied across time-since-vaccination analyses. † Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test in analysis of effectiveness against infection, and one-to-five in analysis of effectiveness against hospitalization and death. ‡ Vaccine effectiveness was estimated using the test-negative, case-control study design. 9,10 § Severity, 21 criticality, 21 and fatality 22 were defined as per World Health Organization guidelines. ¶ Confidence interval could not be estimated using conditional logistic regression because of zero events among those vaccinated. Alternatively, the confidence interval was estimated using the standard error of the crude odds ratio after adding 0.5 to each of the number of vaccinated cases and number of unvaccinated cases. Abbreviations: CI, confidence interval; PCR, polymerase chain reaction. * In each analysis for a specific time-since-vaccination stratum, we included only those vaccinated in this specific time-since-vaccination stratum and those unvaccinated. Only matched pairs of PCR-positive and PCR-negative persons, in which both members of the pair were either unvaccinated or fell within each time-since-vaccination stratum have been included in the corresponding vaccine effectiveness estimate. Thus, the number of cases (and controls) varied across time-since-vaccination analyses. † A symptomatic infection was defined as a PCR-positive test conducted because of clinical suspicion due to presence of symptoms compatible with a respiratory tract infection. ‡ An asymptomatic infection was defined as a PCR-positive test conducted with no reported presence of symptoms compatible with a respiratory tract infection, that is the PCR testing was done as part of a survey or a random testing campaign. § Cases and controls were matched one-to-two by sex, 10-year age group, nationality, reason for PCR testing, and calendar week of PCR test in analysis of effectiveness against infection, and one-to-five in analysis of effectiveness against hospitalization and death. ¶ Vaccine effectiveness was estimated using the test-negative, case-control study design. 9, 10