key: cord-0278977-8t4rnfyu authors: Altarawneh, H.; Chemaitelly, H.; Tang, P.; Hasan, M. R.; Qassim, S.; Ayoub, H. H.; AlMukdad, S.; YASSINE, H. M.; Benslimane, F.; Al Khatib, H. A.; 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.; Abu-Raddad, L. J. title: Protection afforded by prior infection against SARS-CoV-2 reinfection with the Omicron variant date: 2022-01-06 journal: nan DOI: 10.1101/2022.01.05.22268782 sha: 8d3fadf27789da91b60a3bcc8f885abc504c42d8 doc_id: 278977 cord_uid: 8t4rnfyu BACKGROUND: Natural SARS-CoV-2 infection elicits strong protection against reinfection with the Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2) variants. However, the Omicron (B.1.1.529) variant harbors multiple mutations that can mediate immune evasion. We estimated effectiveness of prior infection in preventing reinfection (PES) with Omicron and other SARS-CoV-2 variants in Qatar. METHODS: PES was estimated using the test-negative, case-control study design, employing a methodology that was recently investigated and validated for derivation of robust estimates for PES. Cases (PCR-positive persons with a variant infection) and controls (PCR-negative persons) were exact-matched by sex, 10-year age group, nationality, and calendar time of PCR test, to control for known differences in the risk of exposure to SARS-CoV-2 infection in Qatar. RESULTS: PES against symptomatic reinfection was estimated at 90.2% (95% CI: 60.2-97.6) for Alpha, 84.8% (95% CI: 74.5-91.0) for Beta, 92.0% (95% CI: 87.9-94.7) for Delta, and 56.0% (95% CI: 50.6-60.9) for Omicron. Only 1 Alpha, 2 Beta, 0 Delta, and 2 Omicron reinfections progressed to severe COVID-19. None progressed to critical or fatal COVID-19. PES against hospitalization or death due to reinfection was estimated at 69.4% (95% CI: -143.6-96.2) for Alpha, 88.0% (95% CI: 50.7-97.1) for Beta, 100% (95% CI: 43.3-99.8) for Delta, and 87.8% (95% CI: 47.5-97.1) for Omicron. CONCLUSIONS: Protection afforded by prior infection in preventing symptomatic reinfection with Alpha, Beta, or Delta is robust, at about 90%. While such protection against reinfection with Omicron is lower, it is still considerable at nearly 60%. Prior-infection protection against hospitalization or death at reinfection appears robust, regardless of variant. Natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection elicits strong protection against reinfection with the Alpha (B.1.1.7), 1,2 Beta (B.1.351), 1 with Omicron and other SARS-CoV-2 variants in Qatar. This study was conducted in the resident population of Qatar, applying the test-negative, casecontrol study design [4] [5] [6] to investigate the protection afforded by prior SARS-CoV-2 infection in preventing reinfection with SARS-CoV-2 variants. Effectiveness of prior infection in preventing reinfection (PES) was defined as the proportional reduction in susceptibility to infection among those with prior infection versus those without. 6, 7 The test-negative methodology was recently investigated and validated for the specific derivation of rigorous and robust estimates for SARS-CoV-2 PES. 6 Coronavirus Disease 2019 (COVID-19) laboratory testing, vaccination, clinical infection data, and related demographic details were extracted from the national, federated SARS-CoV-2 databases that include all polymerase chain reaction (PCR) testing, COVID-19 vaccinations, and COVID-19 hospitalizations and deaths in Qatar since the start of the pandemic, with no missing information on variables included in this study. Every PCR test conducted in Qatar is classified based on the reason for testing (clinical symptoms, contact tracing, surveys or random testing campaigns, individual requests, routine All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint healthcare testing, pre-travel, at port of entry, or other). Qatar has unusually young, diverse demographics, in that only 9% of its residents are ≥50 years of age, and 89% are expatriates from over 150 countries. 8, 9 Nearly all individuals were vaccinated in Qatar, however, vaccinations performed elsewhere were still recorded in the health system at the port of entry upon arrival to Qatar per country requirements. exact matched in a ratio of one-to-five by sex, 10-year age group, nationality, and calendar week of the PCR test ( Figure 1 and Table 1 ). Infection with Alpha, Beta, or Delta variants was ascertained using real-time reverse-transcription PCR (RT-qPCR) genotyping of the positive clinical samples (Section S1). 11, 12 A similar methodology was applied to estimate PES against the Omicron 10 (B.1.1.529) variant. However, cases (PCR-positive persons with Omicron infection) and controls (PCR-negative persons) identified between December 23 and January 2, 2022, the time during which the Omicron epidemic wave was exponentially growing in Qatar, were exact matched in a ratio of one-to-three by sex, 10-year age group, nationality, and calendar day of the PCR test (rather than calendar week of the PCR test; Figure 2 and Table 2 ). A SARS-CoV-2 infection with the Omicron variant was proxied as an S-gene "target failure" case using the TaqPath COVID-19 Combo Kit platform (Thermo Fisher Scientific, USA 13 ) applying the criterion of an RT-qPCR Ct value ≤30 for both the N and ORF1ab genes, but a negative outcome for the S gene. All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint Description of laboratory methods for the RT-qPCR testing and variant ascertainment are found in Section S1. All PCR testing was conducted at the Hamad Medical Corporation Central Laboratory or at Sidra Medicine Laboratory, following standardized protocols. Matching of cases and controls was performed to control for known differences in the risk of exposure to SARS-CoV-2 infection in Qatar. 9, [14] [15] [16] [17] Only cases with an RT-qPCR cycle threshold (Ct) value ≤30 and individuals tested because of clinical suspicion, that is presence of symptoms compatible with a respiratory tract infection, were included in analysis. These criteria were applied to ensure that PES is estimated against reinfections with at least some symptomatic disease and epidemiological relevance, as often reinfections occur with negligible symptoms and high Ct values, which are of less public health significance. 18 Only the first PCR-positive test for a specific variant of interest was included for each case. A control was defined as the first PCR-negative test for any individual tested for clinical suspicion during the study period. [19] [20] [21] [22] [23] Prior infection was defined as a PCR-confirmed infection ≥90 days before a new PCR-positive test. 7, 24 Individuals PCR-positive during the 90 days preceding the PCR test were therefore excluded from both cases and controls. These inclusion and exclusion criteria were implemented to minimize different types of potential bias, as informed by prior analyses. 20 Each person who had a PCR-positive 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. Classification of COVID-19 case severity (acute-care hospitalization), 25 criticality (intensivecare-unit (ICU) hospitalization), 25 and fatality 26 followed World Health Organization (WHO) All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint guidelines, and assessments were made by trained medical personnel using individual chart reviews (Section S2). The latter protocol for infection severity assessment was applied for Alpha, Beta, and Delta cases. However, with the recency of the Omicron epidemic wave, assessment of severity, criticality, and fatality of Omicron cases was completed for only a small number of cases. Therefore, only for Omicron cases, any acute-bed hospital admission associated with infection was used as a proxy for COVID-19 severity, and any ICU-bed hospital admission associated with infection was used as a proxy for COVID-19 criticality. Alpha, Beta, Delta, and Omicron cases that progressed to severe, 25 critical, 25 or fatal 26 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. Effectiveness of prior infection in preventing severe, critical, or fatal COVID-19 reinfection was also estimated, applying the same methodology. Here, cases (PCR-positive persons with a variant infection that progressed to a severe, critical, or fatal COVID-19) were exact matched to controls (PCR-negative persons) using the matching criteria specified above for each variant type. 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 were examined for the selection of cases and controls and ascertainment of prior infection status. However, only matched samples of cases and controls All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint were included in the analysis. Cases and controls were described using frequency distributions and measures of central tendency and compared using standardized mean differences (SMDs). SMD is defined as the difference in the mean of a covariate between groups divided by the pooled standard deviation, with SMD <0.1 indicating optimal balance across groups. Odds ratios and associated 95% confidence intervals (CIs) were derived using conditional logistic regression, factoring the matching in the study design. This analytical approach minimizes potential bias that could arise due to variation in epidemic phase 4, 27 or other confounders. 9,14-17,28,29 CIs were not adjusted for multiplicity. Interactions were not investigated. Two sensitivity analyses were conducted to assess the robustness of estimates of PES. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint for Delta, and 56.0% (95% CI: 50.6-60.9) for Omicron. Sensitivity analyses, adjusting for vaccination status or excluding vaccinated subjects from the analysis, confirmed the study results (Table 3) , as expected for this study design, which is robust, irrespective of the approach employed to control for vaccine-induced immunity. 6 Only 1 Alpha, 2 Beta, 0 Delta, and 2 Omicron reinfections progressed to severe COVID-19 ( Omicron. Protection afforded by prior infection in preventing symptomatic reinfection with Alpha, Beta, or Delta is robust, at about 90%, confirming earlier estimates. 1-3 While such protection against reinfection with Omicron is lower, it is still considerable at nearly 60%. Prior-infection protection against hospitalization or death at reinfection appears robust, regardless of variant. Individual-level data on co-morbid 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 co-morbid conditions. Only 9% of the population of Qatar are ≥50 years of age, 8, 9 and 60% are young, expatriate craft and manual workers working in mega-development projects. 16, 17, 30 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. Matching of cases and controls on age may have indirectly and partially adjusted for All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint presence of co-morbidities. With the young population of Qatar, our findings may not be generalizable to other countries where elderly citizens constitute a larger proportion of the total population. PES was assessed using an observational, test-negative, case-control study design, 6 rather than a cohort study design where individuals are followed up over time. However, the cohort study design applied in earlier analyses to estimate PES in the same population of Qatar yielded findings similar to those of the test-negative case-control design, 1,2,6,7,31 supporting the validity of this design in estimating PES. It even appears that the test-negative study design may be less susceptible to some forms of bias than the cohort study design. 6 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 in both the main and sensitivity analyses. Estimates for the effectiveness of prior infection against reinfection with the Alpha and Beta variants were also consistent and similar to those generated earlier in the same population of Qatar using cohort study designs. 1, 2 All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the article. HNA and HC co-designed the study, performed the statistical analyses, and co-wrote the first draft of the article. LJA conceived and co-designed the study, led the statistical analyses, and cowrote 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. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint 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. (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 preprint this version posted January 6, 2022. § SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. An SMD<0.1 indicates optimal balance in matching. ¶ SMD is for the mean difference between groups divided by the pooled standard deviation. **Cases and controls were exact matched using calendar week of PCR test, but we opted to report the distribution by calendar month for brevity. Accordingly, some cases and controls who were tested in the same week may appear in different calendar months. Abbreviations: IQR, interquartile range; PCR, polymerase chain reaction; SMD, standardized mean difference. * Cases and controls were matched one-to-three by sex, 10-year age group, nationality, and PCR test date. † Nationalities were chosen to represent the most populous groups in Qatar. ‡ These comprise 44 other nationalities in Qatar. § SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. An SMD<0.1 indicates adequate matching. ¶ SMD is for the mean difference between groups divided by the pooled standard deviation. All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; Figure 1 ), and one-to-three by sex, 10-year age group, nationality, and PCR test date in the Omicron analysis (December 23, 2021-Jan 2, 2022; Figure 2 ). † Cases and controls were exact matched one-to-five by sex, 10-year age group, nationality, and calendar week of PCR test in the Alpha, Beta, and Delta analyses (March 23-November 18, 2021; Figure 3 ), and one-to-three by sex, 10-year age group, nationality, and PCR test date in the Omicron analysis (December 23, 2021-Jan 2, 2022; Figure 4 ). ‡ Effectiveness of prior infection in preventing reinfection was estimated using the test-negative, case-control study design. 6 § Severity, criticality, and fatality of Alpha, Beta, and Delta cases were defined as per World Health Organization guidelines (Methods and Section S2). With the recency of the Omicron epidemic wave in Qatar, assessment of severity, criticality, and fatality of Omicron cases was completed for only a small number of cases. Therefore, any acute-bed hospital admission associated with Omicron infection was used as a proxy for COVID-19 severity. Any ICU-bed hospital admission associated with Omicron infection was used as a proxy for COVID-19 criticality. ¶ The confidence interval could not be estimated using conditional logistic regression because of zero events among those with prior infection. Alternatively, the confidence interval was estimated using the standard error of the crude odds ratio after adding 0.5 to each number of cases with and without prior infection. All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint Section S1. Laboratory methods Nasopharyngeal and/or oropharyngeal swabs were collected for polymerase chain reaction All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. All the variant RT-qPCR screening was conducted at the Sidra Medicine Laboratory following standardized protocols. Surveillance for Omicron infection was performed using the TaqPath COVID-19 Combo Kit platform (Thermo Fisher Scientific, USA 9 ) applying the criterion of an RT-qPCR Ct value ≤30 for both the N and ORF1ab genes, but a negative outcome for the S gene (S-gene "target failure"). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 3 All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. All rights reserved. No reuse allowed without permission. (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 preprint this version posted January 6, 2022. ; https://doi.org/10.1101/2022.01.05.22268782 doi: medRxiv preprint National Study Group for Covid Epidemiology. Efficacy of Natural Immunity against SARS-CoV-2 Reinfection with the Beta Variant Introduction and expansion of the SARS-CoV-2 B.1.1.7 variant and reinfections in Qatar: A nationally representative cohort study Duration of SARS-CoV-2 Natural Immunity and Protection against the Delta Variant: A Retrospective Cohort Study The test-negative design for estimating influenza vaccine effectiveness Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls Estimating protection afforded by prior infection in preventing reinfection: Applying the test-negative study design SARS-CoV-2 antibody-positivity protects against reinfection for at least seven months with 95% efficacy Characterizing the Qatar advancedphase SARS-CoV-2 epidemic Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar TaqPath™ COVID-19 CE-IVD RT-PCR Kit instructions for use Mathematical modeling of the SARS-CoV-2 epidemic in Qatar and its impact on the national response to COVID-19 SARS-CoV-2 seroprevalence in the urban population of Qatar: An analysis of antibody testing on a sample of 112 SARS-CoV-2 Infection Is at Herd Immunity in the Majority Segment of the Population of Qatar Herd Immunity against Severe Acute Respiratory Syndrome Coronavirus 2 Infection in 10 Communities Effect of vaccination and of prior infection on infectiousness of vaccine breakthrough infections and reinfections Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar Waning of mRNA-1273 vaccine effectiveness against SARS-CoV-2 infection in Qatar 26. World Health Organization. International guidelines for certification and classification (coding) of COVID-19 as cause of death Is it necessary to adjust for calendar time in a test negative design?: Responding to: Jackson ML, Nelson JC. The test negative design for estimating influenza vaccine effectiveness Analysis of matched case-control studies Assessment of the Risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reinfection in an Intense Reexposure Setting Section S2. COVID-19 severity, criticality, and fatality classification COVID-19) disease was defined per the World health Organization (WHO) classification as a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected person with "oxygen saturation of <90% on room air, and/or respiratory rate of old), and/or signs of severe respiratory distress (accessory muscle use and inability to complete full sentences, and, in children, very severe chest wall indrawing, grunting, central cyanosis, or presence of any other general danger signs)". 10 Detailed WHO criteria for classifying SARS-CoV-2 infection severity can be Critical COVID-19 disease was defined per WHO classification as a SARS-CoV-2 infected person with "acute respiratory distress syndrome, sepsis, septic shock, or other conditions that would normally require the provision of life sustaining therapies such as mechanical ventilation (invasive or non-invasive) or vasopressor therapy". 10 Detailed WHO criteria for classifying SARS-CoV-2 infection criticality can be No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. References 1. Multiplexed RT-qPCR to screen for SARS-COV-2 B.1.1.7, B.1.351, and P.1 variants of concern V.3. dx National Study Group for Covid Vaccination. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar Qatar viral genome sequencing data. Data on randomly collected samples One Year of SARS-CoV-2: Genomic Characterization of COVID-19 Outbreak in Qatar Real-Time SARS-CoV-2 Genotyping by High-Throughput Multiplex PCR Reveals the Epidemiology of the Variants of Concern in Qatar Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar COVID-19 (SARS-CoV-2) outbreak monitoring using wastewater-based epidemiology in Qatar 11. World Health Organization. International guidelines for certification and classification (coding) of COVID-19 as cause of death 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 Table of contents