Effects of Prior Infection and Vaccination on Symptomatic Omicron Infections | NEJM

Study population and data sources

The study was conducted among the resident population of Qatar. We analyzed information from federated national databases regarding vaccination against Covid-19, laboratory tests, hospitalizations and deaths. This data was extracted from the National Integrated 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, the results of all polymerase chain reaction (PCR) tests and, most recently, rapid antigen tests performed in healthcare facilities on or after January 5, 2022. date.

All PCR tests (but not rapid antigen tests) carried out in Qatar are classified according to 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 has an unusually young and diverse population – only 9% of its residents are 50 or older and 89% are expats from over 150 countries.ten Qatar launched its Covid-19 vaccination program in December 2020 with the BNT162b2 and mRNA-1273 vaccines.11 Other descriptions of the study population and national databases have been reported previously.4.10-15

study design

The study evaluated the efficacy of prior infection, vaccination with BNT162b2 or mRNA-1273 and hybrid immunity (prior 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 efficacy estimates were derived by comparing the odds of previous infection or vaccination or both among case participants (people with a positive PCR test) with those of the controls (PCR negative people).2.15-18 We also assessed efficacy against any severe, critical or fatal cases of Covid-19.

To estimate efficacy against symptomatic infection, we exactly matched cases and controls that were identified from December 23, 2021 to February 21, 2022. Case participants and controls were matched in a 1:1 ratio according to gender, 10 year age group, nationality and calendar week of the PCR test. The matching was done to control for known differences in the risk of exposure to SARS-CoV-2 in Qatar.10,19,20 Matching on these factors has previously been shown to provide adequate control for differences in SARS-CoV-2 exposure risk in studies of different designs, all of which involved control groups, such as case studies. – negative test controls.11,12,15,21,22 To assess efficacy against any severe, critical or fatal case of Covid-19, we used a matching ratio of 1:5 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 people with no record of a positive PCR test during the study period. Only PCR tests performed due to clinical symptoms were used in the analyses.

SARS-CoV-2 reinfection is conventionally defined as documented infection that occurs at least 90 days after a previous infection, to avoid misclassification of prolonged PCR positivity as reinfection if a shorter time interval is used.2.23 Prior infection was therefore defined as a positive PCR test that occurred at least 90 days before the PCR test used in the study. Tests for people who had positive PCR tests that occurred 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, as they occurred before the wave of omicron 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 occurring 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 the development of immunity after vaccination4.14 and to minimize different types of potential biases, as indicated by previous analyzes in the same population.12.22 Each control that met the inclusion criteria and 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 the type of exposure: previous infection and absence of vaccination, vaccination with two doses and absence of previous infection, vaccination with two doses and previous infection, vaccination with three doses and absence of previous infection, and three-dose vaccination and previous infection. . The groups were defined based on the status of previous immunological events (infection or previous vaccination) at the time of the PCR test.

Bass classification,8 critical,8 and fatal9 Covid-19 cases followed World Health Organization guidelines and assessments were carried out by trained medical staff using individual chart reviews under a national patient protocol hospitalized with Covid-19. Details regarding the severity, criticality and classification of Covid-19 deaths are provided in Section S1 of the Supplementary Annex.

Laboratory methods and determination of subvariants

The big omicron wave in Qatar started on December 19, 2021 and peaked in mid-January 2022.2-4 A total of 315 SARS-CoV-2 positive random samples collected from December 19, 2021 to January 22, 2022 underwent viral whole genome sequencing on a GridION sequencing device (Nanopore Technologies). Of these samples, 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 of the S gene,24 to identify BA.1 and BA.2 infections. An S gene target defect was used as a proxy for BA.1 infection, and a non-gene S target defect was used as a proxy for BA.2 infection. Additional details regarding laboratory methods for real-time quantitative reverse transcriptase-PCR 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 a waiver of informed consent. The reporting of this study follows the guidelines on strengthening the reporting of observational studies in epidemiology (Table S1). The study funders had no role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. All authors contributed to the collection and acquisition of the data, the discussion and interpretation of the results, and the drafting of the manuscript. All authors have read and approved the final manuscript.

Statistical analyzes

Although all PCR test records were reviewed for case and control selection, only matched samples were analyzed. Cases and controls were described using frequency distributions and measures of central tendency and compared using 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, values ​​less than 0, 1 indicating an adequate match.25

Odds ratios, which compared the likelihood of previous infection or vaccination or both among cases with that among controls, and the associated 95% confidence intervals were derived using regression conditional logistics. This analytical approach, which also incorporates matching according to the calendar week of the PCR test, minimizes the potential biases due to the variation of the epidemic phase.16.26 and the deployment of vaccination during the study period.16.26 Confidence intervals have not been adjusted for multiplicity and therefore should not be used to infer definitive differences between exposure groups. Interactions have not been studied. Efficacy and associated 95% confidence intervals were calculated as 1 minus the odds ratio of infection or prior vaccination, or both, among cases versus controls.16.17 The reference group for all estimates included people with no previous infection and no vaccinations.

Additional analysis was conducted to investigate the effects of prior infection, two-dose vaccination, and three-dose vaccination as a function of time since the immunological event (prior infection or vaccination). This analysis used the same approach as the primary analysis, but stratified by 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 test. A sensitivity analysis of efficacy against any symptomatic infection with omicron was performed, but prior positive tests being based on positive PCR as well as positive rapid antigen tests, to determine whether exclusion of rapid tests positive antigens could have biased our estimates. Statistical analyzes were performed using Stata/SE software, version 17.0 (StataCorp).

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