Population study and data sources
The study was conducted on the population residing in Qatar. We analyzed information from standardized national databases regarding Covid-19 vaccination, laboratory testing, hospitalization and death. This data was retrieved from a nationwide integrated digital health information platform. The databases included all data related to SARS-CoV-2 and associated demographic information since the beginning of the epidemic. These databases include, with no missing information, the results of all PCR tests and, most recently, a rapid antigen test performed in healthcare facilities on or after January 5, 2022.
All PCR tests (but not the rapid antigen test) that are performed in Qatar are categorized on the basis of symptoms and the reason for the test. Of all the PCR tests performed during this study, 19.2% were performed due to clinical symptoms. Qatar’s young population is extraordinarily diverse – only 9% of its residents are 50 years of age or older, and 89% of expats are from more than 150 countries.10 Qatar launched its Covid-19 vaccination program in December 2020 with two vaccines, BNT162b2 and mRNA-1273.11 Other descriptions of the study community and national databases have been previously reported.4, 10 – 15
The study evaluated the efficacy of previous infection, vaccination with BNT162b2 or mRNA-1273, and hybrid immunity (previous infection and vaccination) against cross-infection with BA.1, BA.2, and any omicron infection.2,15-18 We used a control-negative test design, in which efficacy estimates were derived by comparing the odds of prior infection, vaccination, or both among case participants (people with a positive PCR test) with those among the controls (PCR-negative people).2,15-18 We also evaluated the efficacy against any serious, critical or fatal case of Covid-19.
To estimate efficacy against symptomatic infection, we matched cases and controls identified from December 23, 2021 through February 21, 2022. Case and control participants were matched in a 1:1 ratio according to sex, 10-year age group, nationality, and calendar week of PCR testing. Matching was performed to control for known differences in the risk of exposure to SARS-CoV-2 in Qatar.10, 19, 20 It has previously been shown that matching according to these factors provides adequate control for differences in risk of exposure to SARS-CoV-2 in studies of different designs, all of which included control groups, such as test negative and case-control studies.11,12,15,21,22 To assess efficacy against any serious, critical, or fatal case of Covid-19, we used a 1:5 matching ratio to improve the statistical accuracy of the estimates.
The first PCR-positive test identified for an individual participant during the study period, but all PCR-negative tests were included. Controls included subjects who had no history of a positive PCR test during the study period. Only polymerase chain reaction (PCR) tests performed due to clinical symptoms were used in the analyses.
Re-infection with SARS-CoV-2 is traditionally defined as a documented infection occurring at least 90 days after the previous infection, in order to avoid misclassification of prolonged PCR positivity as re-infection if a shorter period of time is used.2,23 Previous infection was therefore defined as a positive PCR test that occurred at least 90 days prior to the PCR test used in the study. Tests in subjects who underwent positive PCR tests within 90 days prior to 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, because they occurred before the omicron wave in Qatar.2-4
PCR tests for people who received vaccines other than BNT162b2 or mRNA-1273 and tests for people who received mixed vaccines were excluded from the analyses. Tests performed 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 building of immunity after vaccination4,14 and to reduce the different types of potential bias, according to previous analyzes in the same population.12, 22 Each control that met the inclusion criteria and could match a condition was included in the analyses.
We compared five groups with the group that had neither previous infection nor vaccination. The five groups were characterized by the type of exposure: previous infection and no vaccination, vaccination with two doses and no previous infection, vaccination with two doses and previous infection, vaccination with three doses and no previous infection, vaccination with three doses and previous infection. Clusters were determined based on the status of previous immune events (previous infection or vaccination) at the time of PCR testing.
severe rating,8 critical,8 and killer9 Covid-19 cases followed WHO guidelines, and assessments were performed by trained medical personnel using individual chart reviews as part of a national protocol applied to hospitalized patients with Covid-19. Details regarding the classification of Covid-19 severity, severity, and mortality are provided in Section S1 in the Supplementary Appendix.
Laboratory methods and sub-confirmation
The Omicron Big Wave began in Qatar on December 19, 2021, and culminated in mid-January 2022.2-4 315 random SARS-CoV-2-positive samples were collected from December 19, 2021 through January 22, 2022, and subjected to complete viral genome sequencing on a network sequencer (Nanopore Technologies). Of these samples, 300 (95.2%) were confirmed as omicron infection and 15 (4.8%) were delta (or B.1.617.2)1 infections.2-4 Of the 286 omicron infections with confirmed subcase 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 the spiky (S) gene for SARS-CoV-2 and the 69-70del mutation in the S gene,24 To identify BA.1 and BA.2 injuries. Failure of the S gene target was used as a surrogate for BA.1 infection, and failure of the non-gene target S was used as a surrogate for BA.2 infection. Additional details regarding laboratory methods for quantitative real-time reverse transcriptase testing are provided in Section S2.
This retrospective study was approved by the Institutional Review Boards of Hamad Medical Corporation and Weill Cornell Medicine-Qatar, with informed consent waived. Reporting for this study follows the guidelines for strengthening the reporting of observational studies in the Epidemiology Guidelines (Table S1). Study funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. All authors contributed to data collection and acquisition, discussion and interpretation of results, and writing of the manuscript. All authors read and approved the final manuscript.
Although all PCR test records were screened for selection of cases and controls, only matched samples were analyzed. Cases and controls were described using frequency distributions and measures of central tendency and compared using standard mean differences. The standard 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 less than 0.1 indicating adequate matching.25
Odds ratios, which compared the odds of infection, previous vaccination, or both between cases with those between controls, and 95% of the associated confidence intervals were derived using conditional logistic regression. This analytical approach, which also includes matching according to the PCR test calendar week, reduces potential bias due to variation in the stage of the epidemic.16,26 And start vaccination during the study period.16,26 Confidence intervals were not adjusted for multiplicity, and therefore should not be used to infer definitive differences between exposure groups. Interactions have not been investigated. Efficacy and associated 95% confidence intervals (CIs) were calculated as 1 minus the odds ratio for previous infection, vaccination, or both among cases compared to controls.16, 17 The reference set of all estimates included people with neither previous infection nor vaccine.
Additional analysis was performed to check the effects of previous infection, two-dose vaccination, and three-dose vaccination as a function of time since the immune event (previous infection or vaccination). This analysis used the same approach as the primary analysis, but stratified according to time since the most recent immunological event.
A person was considered to have had a previous positive test if that test was positive by PCR assay. Sensitivity analysis for efficacy against any symptomatic omicron infection, but with previous positive test based on positive PCR as well as positive rapid antigen tests, was performed to check whether exclusion of positive rapid antigen tests might bias our estimates. Statistical analyzes were performed using Stata/SE software, version 17.0 (StataCorp).