Study Population and Data Sources
The study was conducted in the resident population of Qatar. We analyzed information from the national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death. These data were retrieved from the integrated nationwide digital-health information platform. The databases included all SARS-CoV-2–related data and associated demographic information since the start of the pandemic. These databases include, with no missing information, results of all polymerase-chain-reaction (PCR) testing and, more recently, rapid antigen testing conducted at health care facilities on or after January 5, 2022.
All PCR testing (but not rapid antigen testing) performed in Qatar is classified on the basis of symptoms and the reason for testing. Of all the PCR tests conducted during this study, 19.2% were performed because of clinical symptoms. Qatar has an unusually young, diverse population — only 9% of its residents are 50 years of age or older, and 89% are expatriates from more than 150 countries.10 Qatar launched its Covid-19 vaccination program in December 2020 with the BNT162b2 and mRNA-1273 vaccines.11 Further descriptions of the study population and the national databases have been reported previously.4,10-15
The study assessed the effectiveness of previous infection, vaccination with BNT162b2 or mRNA-1273, and hybrid immunity (previous infection and vaccination) against symptomatic infection with BA.1, BA.2, and any omicron infection.2,15-18 We used a test-negative, case–control design, in which effectiveness estimates were derived by comparing the odds of previous infection or vaccination or both among case participants (persons with a positive PCR test) with that among controls (PCR-negative persons).2,15-18 We also assessed effectiveness against any severe, critical, or fatal case of Covid-19.
To estimate the effectiveness against symptomatic infection, we exactly matched cases and controls that were identified from December 23, 2021, through February 21, 2022. Case participants and controls were matched in a 1:1 ratio according to sex, 10-year age group, nationality, and calendar week of PCR test. Matching was performed to control for known differences in the risk of SARS-CoV-2 exposure in Qatar.10,19,20 Matching according to these factors was previously shown to provide adequate control of differences in the risk of SARS-CoV-2 exposure in studies of different designs, all of which involved control groups, such as test-negative, case–control studies.11,12,15,21,22 To assess effectiveness against any severe, critical, or fatal case of Covid-19, we used a 1:5 matching ratio to improve the statistical precision of the estimates.
Only the first PCR-positive test that was identified for an individual participant during the study period was included, but all PCR-negative tests were included. Controls included persons with no record of a PCR-positive test during the study period. Only PCR tests conducted because of clinical symptoms were used in the analyses.
SARS-CoV-2 reinfection is conventionally defined as a documented infection that occurs at least 90 days after an earlier infection, to avoid misclassification of prolonged PCR positivity as reinfection if a shorter time interval is used.2,23 Previous infection was therefore defined as a PCR-positive test that occurred at least 90 days before the PCR test used in the study. Tests for persons who had PCR-positive tests that occurred within 90 days before the PCR test used in the study were excluded. Accordingly, previous infections in this study were considered to be due to variants other than omicron, since they occurred before the omicron wave in Qatar.2-4
PCR tests for persons who received vaccines other than BNT162b2 or mRNA-1273 and tests for persons who received mixed vaccines were excluded from the analyses. Tests that occurred within 14 days after a second dose or 7 days after a third dose of vaccine were excluded. These inclusion and exclusion criteria were implemented to allow for build-up of immunity after vaccination4,14 and to minimize different types of potential bias, as informed by earlier analyses in the same population.12,22 Every control that met the inclusion criteria and that could be matched to a case was included in the analyses.
We compared five groups with the group that had no previous infection and no vaccination. The five groups were characterized by type of exposure: previous infection and no vaccination, two-dose vaccination and no previous infection, two-dose vaccination and previous infection, three-dose vaccination and no previous infection, and three-dose vaccination and previous infection. The groups were defined on the basis of the status of previous immunologic events (previous infection or vaccination) at the time of the PCR test.
Classification of severe,8 critical,8 and fatal9 Covid-19 cases followed World Health Organization guidelines, and assessments were made by trained medical personnel with the use of individual chart reviews as part of a national protocol applied to hospitalized patients with Covid-19. Details regarding Covid-19 severity, criticality, and fatality classification are provided in Section S1 in the Supplementary Appendix.
Laboratory Methods and Subvariant Ascertainment
The large omicron wave in Qatar started on December 19, 2021, and peaked in mid-January 2022.2-4 A total of 315 random SARS-CoV-2–positive specimens collected from December 19, 2021, through January 22, 2022, underwent viral whole-genome sequencing on a GridION sequencing device (Nanopore Technologies). Of these specimens, 300 (95.2%) were confirmed to be omicron infections and 15 (4.8%) to be delta (or B.1.617.2)1 infections.2-4 Of the 286 omicron infections with confirmed subvariant status, 68 (23.8%) were BA.1 and 218 (76.2%) were BA.2.
We used the TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific), which tests for the spike (S) gene of SARS-CoV-2 and the 69-70del mutation in the S gene,24 to identify BA.1 and BA.2 infections. An S-gene target failure was used as a proxy for BA.1 infection, and a non–S-gene target failure was used as a proxy for BA.2 infection. Additional details regarding laboratory methods for real-time reverse-transcriptase–quantitative PCR testing are provided in Section S2.
This retrospective study was approved by the institutional review boards at Hamad Medical Corporation and Weill Cornell Medicine–Qatar, with a waiver of informed consent. The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology guidelines (Table S1). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. All the authors contributed to data collection and acquisition, discussion and interpretation of the results, and the writing of the manuscript. All the authors read and approved the final manuscript.
Although all records of PCR testing were examined for selection of cases and controls, only matched samples were analyzed. Cases and controls were described with the use of frequency distributions and measures of central tendency and compared with the use of standardized mean differences. The standardized mean difference was defined as the difference between the mean value of a covariate in one group and the corresponding mean value of a covariate in the other group, divided by the pooled standard deviation, with values of less than 0.1 indicating adequate matching.25
Odds ratios, which compared the odds of previous infection or vaccination or both among cases with that among controls, and associated 95% confidence intervals were derived with the use of conditional logistic regression. This analytic approach, which also incorporated matching according to calendar week of PCR test, minimizes potential bias due to variation in epidemic phase16,26 and roll-out of vaccination during the study period.16,26 Confidence intervals were not adjusted for multiplicity and therefore should not be used to infer definitive differences among exposure groups. Interactions were not investigated. Effectiveness and associated 95% confidence intervals were calculated as 1 minus the odds ratio of previous infection or vaccination or both among cases as compared with controls.16,17 The reference group for all estimates included persons with no previous infection and no vaccination.
An additional analysis was conducted to investigate the effects of previous infection, two-dose vaccination, and three-dose vaccination as a function of time since the immunologic event (previous infection or vaccination). This analysis used the same approach as the primary analysis, but with stratification according to time since the most recent immunologic event.
A person was considered to have had a previous positive test if that test was positive by PCR assay. A sensitivity analysis of effectiveness against any symptomatic omicron infection was conducted, but with previous positive testing being based on positive PCR as well as positive rapid antigen tests, to investigate whether exclusion of rapid antigen–positive tests could have biased our estimates. Statistical analyses were performed with the use of Stata/SE software, version 17.0 (StataCorp).