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The protection conferred by natural immunity, vaccination, and both against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the BA.1 or BA.2 sublineages of the omicron (B.1.1.529) variant is unclear.
We conducted a national, matched, test-negative, case–control study in Qatar from December 23, 2021, through February 21, 2022, to evaluate the effectiveness of vaccination with BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna), natural immunity due to previous infection with variants other than omicron, and hybrid immunity (previous infection and vaccination) against symptomatic omicron infection and against severe, critical, or fatal coronavirus disease 2019 (Covid-19).
The effectiveness of previous infection alone against symptomatic BA.2 infection was 46.1% (95% confidence interval [CI], 39.5 to 51.9). The effectiveness of vaccination with two doses of BNT162b2 and no previous infection was negligible (−1.1%; 95% CI, −7.1 to 4.6), but nearly all persons had received their second dose more than 6 months earlier. The effectiveness of three doses of BNT162b2 and no previous infection was 52.2% (95% CI, 48.1 to 55.9). The effectiveness of previous infection and two doses of BNT162b2 was 55.1% (95% CI, 50.9 to 58.9), and the effectiveness of previous infection and three doses of BNT162b2 was 77.3% (95% CI, 72.4 to 81.4). Previous infection alone, BNT162b2 vaccination alone, and hybrid immunity all showed strong effectiveness (>70%) against severe, critical, or fatal Covid-19 due to BA.2 infection. Similar results were observed in analyses of effectiveness against BA.1 infection and of vaccination with mRNA-1273.
No discernable differences in protection against symptomatic BA.1 and BA.2 infection were seen with previous infection, vaccination, and hybrid immunity. Vaccination enhanced protection among persons who had had a previous infection. Hybrid immunity resulting from previous infection and recent booster vaccination conferred the strongest protection. (Funded by Weill Cornell Medicine–Qatar and others.)
Qatar endured a wave of the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1 that started on December 19, 2021, and peaked in mid-January 2022.2-4 The wave was first dominated by the BA.1 subvariant, but within a few days after the onset of the wave, the BA.2 subvariant predominated (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Although BA.1 and BA.2 remain classified as subvariants of omicron, considerable genetic distance exists between them.5 The protection against these subvariants provided by previous immunity — and whether immunity is induced by previous infection, vaccination, or a hybrid of both — remains to be established.
With the use of data from December 23, 2021, through February 21, 2022, we investigated the protection conferred by previous infection from variants other than omicron, vaccination with two or three doses of the coronavirus disease 2019 (Covid-19) messenger RNA (mRNA) vaccines BNT162b2 (Pfizer–BioNTech)6 or mRNA-1273 (Moderna),7 and hybrid immunity (previous infection and vaccination). Effectiveness against symptomatic BA.1 infection, symptomatic BA.2 infection, and any symptomatic omicron infection was assessed. Protection against any severe (acute-care hospitalization),8 critical (hospitalization in an intensive care unit),8 or fatal9 case of Covid-19 due to BA.1, BA.2, or any omicron infection was also assessed.
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).
From December 23, 2020 (the date that vaccination began in Qatar), through February 21, 2022 (the end of the study), 1,306,862 persons received at least two doses of BNT162b2, and 341,438 of these received a third (booster) dose. The median date of the first dose was May 3, 2021, the median date of the second dose was May 24, 2021, and the median date of the third dose was December 25, 2021. The median interval between the first and second doses was 21 days (interquartile range, 21 to 22), and between the second and third doses was 251 days (interquartile range, 233 to 274). The narrow interquartile range between the first and second doses reflects strict adherence to national policy.
During the study period, 893,671 persons received two doses of mRNA-1273, and 135,050 of these received a third dose. The median date of the first dose was May 28, 2021, the median date of the second dose was June 27, 2021, and the median date of the third dose was January 12, 2022. The median interval between the first and second doses was 28 days (interquartile range, 28 to 30), and between the second and third doses was 236 days (interquartile range, 213 to 260).
The study was based on the total population of Qatar; therefore, the population is representative of the internationally diverse, but young and predominantly male, population of the country (Table S2). Figure S2 shows the process for selecting the populations for the analysis of BNT162b2, and Table 1 shows the characteristics of these populations. Figure S3 shows the process for selecting the populations for the analysis of mRNA-1273, and Table S4 shows the characteristics of these populations.
Read full article here – https://www.nejm.org – https://www.nejm.org/doi/full/10.1056/NEJMoa2203965?query=featured_home