key: cord-0293418-yi3i221e
authors: Abu-Raddad, L. J.; Chemaitelly, H.; Ayoub, H. H.; Tang, P. J.; Hasan, M. R.; Coyle, P.; YASSINE, H. M.; Benslimane, F.; Al-Khatib, H. A.; 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.
title: Protection offered by mRNA-1273 versus BNT162b2 vaccines against SARS-CoV-2 infection and severe COVID-19 in Qatar
date: 2021-11-13
journal: nan
DOI: 10.1101/2021.11.12.21266250
sha: c3e4c4b07142387875a59a5d672198ba9f2153f3
doc_id: 293418
cord_uid: yi3i221e

BACKGROUND: Growing evidence suggests that COVID-19 vaccines differ in effectiveness against breakthrough infection or severe COVID-19, but vaccines have yet to be investigated in controlled studies that head-to-head compare immunity of one to another. This study compared protection offered by the mRNA-1273 (Moderna) vaccine with that of the BNT162b2 (Pfizer-BioNTech) vaccine in Qatar. METHODS: In a population of 1,531,736 vaccinated persons, two matched retrospective cohort studies were designed and used to investigate differences in mRNA-1273 and BNT162b2 vaccine protection, after the first and second doses, from December 21, 2020 to October 20, 2021. RESULTS: After dose 1, cumulative incidence of breakthrough infection was 0.79% (95% CI: 0.75-0.83%) for mRNA-1273-vaccinated individuals and 0.86% (95% CI: 0.82-0.90%) for BNT162b2-vaccinated individuals, 21 days post-injection. Adjusted hazard ratio (AHR) for breakthrough infection was 0.89 (95% CI: 0.83-0.95; p=0.001). AHR was constant in the first two weeks at 1, but it declined to 0.67 (95% CI: 0.57-0.77; p<0.001) in the third week after dose 1. AHR for any severe, critical, or fatal COVID-19 was 0.71 (95% CI: 0.53-0.95; p=0.020). After dose 2, cumulative incidence was 0.59% (95% CI: 0.55-0.64%) for mRNA-1273-vaccinated individuals and 0.84% (95% CI: 0.79-0.89%) for BNT162b2-vaccinated individuals, 180 days post-injection. AHR for breakthrough infection was 0.69 (95% CI: 0.63-0.75; p<0.001) and was largely constant over time after dose 2. AHR for any severe, critical, or fatal COVID-19 was 0.37 (95% CI: 0.10-1.41; p=0.147). CONCLUSIONS: mRNA-1273 vaccination is associated with lower SARS-CoV-2 breakthrough infection and COVID-19 hospitalization and death than BNT162b2 vaccination, but the number of hospitalizations and deaths was exceedingly small for both vaccines. Both vaccines demonstrated strikingly similar patterns of build-up of protection after the first dose and waning of protection after the second dose.

Protection offered by Coronavirus Disease 2019 (COVID- 19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 has been investigated in randomized clinical trials 1, 2 and in observational studies. 3 A growing number of studies suggests that these vaccines differ in effectiveness in preventing breakthrough infection or severe COVID-19. [3] [4] [5] [6] [7] [8] [9] [10] [11] However, protection conferred by these vaccines has not been investigated in controlled studies that directly compare one to another. In this study, we compared the protection conferred by the mRNA-1273 1 (Moderna) vaccine to that of the BNT162b2 2 (Pfizer-BioNTech) vaccine in Qatar, using a matched cohort study design that allows a head-to-head comparison of protection of these two mRNA vaccines.

Hamad Medical Corporation and Weill Cornell Medicine-Qatar Institutional Review Boards approved this retrospective study with waiver of informed consent, since analysis was done on routinely collected data.

This study analyzed the national, federated databases for SARS-CoV-2 infection in the resident population of Qatar, compiled at Hamad Medical Corporation, the main public healthcare provider and the nationally designated provider for all COVID-19 healthcare needs. These databases were constructed through a national electronic platform for health records designed to capture all SARS-CoV-2-related data. These include all polymerase chain reaction (PCR) testing, vaccination records, COVID-19 hospitalizations, infection severity and mortality classifications per World Health Organization (WHO) guidelines, 12,13 in addition to sex, age, and All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint nationality information retrieved from the national registry. Further descriptions of these national databases can be found in previous studies. 6, 8, 9, [14] [15] [16] [17] [18] [19] Qatar has young, diverse demographics. Only 9% of the population are ≥50 years of age and 89% are resident expatriates from more than 150 countries. 14, 20 Qatar launched its mass COVID-19 immunization campaign on December 21, 2020, first using the BNT162b2 2 vaccine, 6, 8 and three months later it added the mRNA-1273 1 vaccine. 8 Immunization with both vaccines followed the US Food and Drug Administration-approved dosing schedule. 1, 2 Vaccination was scaled up in phases to prioritize those most vulnerable to infection or to severe COVID-19. 19 As of , it is estimated that >80% of Qatar's population had received both doses of either mRNA-1273 or BNT162b2. 21 During a vaccination drive spanning nearly a year, Qatar experienced two epidemic waves predominated by the Alpha 22 (B.1.1.7) and Beta 22 (B.1.351) variants, 6, 8, 19 ,23-25 but incidence since July 2021 has been predominated by the Delta 22 (B.1.617.2) variant. 6, 8, 9, 19, [23] [24] [25] Differences in incidence of breakthrough infection following administration of the first and second mRNA-1273 and BNT162b2 vaccine doses up to the study closing date (October 20, 2021) were investigated using two retrospective, matched cohort studies. The first study investigated incidence of breakthrough infection following administration of the first dose of each vaccine and before administration of the second dose. The second study investigated incidence of breakthrough infection in the months following administration of the second dose.

To control for differences in risk of exposure to the infection in Qatar 14,17,26-28 and variant exposure, 6,8,9,19, Investigated primary outcome in both studies was any PCR-positive nasopharyngeal swab regardless of the reason for PCR testing or presence of symptoms. Investigated secondary outcome in both studies was any severe, 12 critical, 12 or fatal 13 breakthrough COVID-19 disease.

Classification of COVID-19 case severity (acute-care hospitalizations), 12 criticality (ICU hospitalizations), 12 and fatality 13 followed WHO guidelines, and assessments were made by trained medical personnel using individual chart reviews. Details of the COVID-19 severity, criticality, and fatality classification are found in Section 1 in Supplementary Appendix.

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Study populations were described using frequency distributions and measures of central tendency. Balance between study cohorts was assessed using standardized mean differences (SMDs), with SMD ≤0.1 indicating adequate matching. 30 The Kaplan-Meier estimator method 31 was used to estimate the cumulative incidence of infection. Cumulative incidence of infection was defined as the proportion of individuals at risk that were identified with a breakthrough infection during follow-up among all eligible individuals in each cohort. Equality of failure functions was assessed using the log-rank test.

Standard errors of failure functions were used to derive 95% confidence intervals (CIs) of the absolute difference in cumulative incidence at different follow-up times.

Incidence rates and corresponding 95% CIs were estimated using a Poisson log-likelihood regression model with the STATA 17.0 32 stptime command. Hazard ratios and corresponding 95% CIs were calculated using Cox regression adjusted for the matching factors with the STATA 17.0 32 stcox command. Shoenfeld residuals and log-log plots confirmed adequacy of the proportional-hazards assumption. 95% CIs were not adjusted for multiplicity. Interactions were not considered. Subgroup analyses were performed to estimate adjusted hazard ratios at different follow-up times.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In all analyses, two-sided p<0.05 indicated statistical significance. Statistical analyses were conducted in STATA/SE version 17.0. 32 STROBE checklist is in Table S1 .

Of 1,531,736 vaccinated persons, 491,875 mRNA-1273-vaccinated individuals and 845,326

BNT162b2-vaccinated individuals met the eligibility criteria for the study, assessing incidence of breakthrough infection after dose 1 ( Figure 1 ). Also, of the 1,531,736 vaccinated persons, 443,416 mRNA-1273-vaccinated individuals and 799,836 BNT162b2-vaccinated individuals met the eligibility criteria for the study, assessing incidence of breakthrough infection after dose 2 ( Figure 1 ).

Baseline characteristics of mRNA-1273-and BNT162b2-vaccinated cohorts that were followed up from the date of dose 1 are presented in Table 1 . Prior to matching, there were small differences in sex, but large differences in age distribution, nationality, and calendar month of dose 1. These differences have arisen because the mass mRNA-1273 immunization campaign started three months after the BNT162b2 campaign; vaccination was prioritized to frontline health workers, persons with severe or multiple chronic conditions, specific occupational groups, such as teachers, and by age; 19 all in a context in which there are associations between age, sex, nationality, and occupation. 14, 17, [26] [27] [28] Baseline characteristics of the mRNA-1273-and BNT162b2-vaccinated cohorts that were followed up from the date of dose 2 are presented in Table 2 . Similar differences were observed for the same reasons as for those followed up from the date of dose 1.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table   1 ). The median date of dose 1 was April 28, 2021. Among mRNA-1273-and BNT162b2vaccinated individuals, 7.4% and 6.5% had a PCR test done during follow-up, respectively. The higher proportion among those vaccinated with mRNA-1273 is a consequence of longer followup with the one-week delayed dose 2 schedule, compared to those BNT162b2 vaccinated.

Among mRNA-1273-vaccinated individuals, 1,752 breakthrough infections were recorded after dose 1 and before dose 2 at a median follow-up of 9 days (IQR: 6-14 days; Figure 1 ; Table 3 ). Of these infections, 68 progressed to severe COVID-19 disease, 7 to critical disease, and 5 to COVID-19 death.

Among BNT162b2-vaccinated individuals, 1,778 breakthrough infections were recorded after dose 1 and before dose 2 at a median follow-up of 10 days (IQR: 6-15 days; Figure 1 ; Table 3 ).

Of these infections, 93 progressed to severe COVID-19 disease, 9 to critical disease, and 7 to COVID-19 death.

There were minimal differences in median age, age distribution, sex, nationality, and calendar month of dose 1 between mRNA-1273 and BNT162b2 breakthrough infections (Table 3) . Most All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint breakthrough infections in both vaccinated cohorts occurred during the large Beta variant wave between March and May 2021. 6, 8, 9, 19, [23] [24] [25] The median date of breakthrough infection was April 14, 2021. Only a minority of infections occurred after June 2021, when the Delta variant predominated. 6, 8, 9, 19, [23] [24] [25] Cumulative incidence of breakthrough infection after dose 1 was estimated at 0.79% (95% CI: Table 4 ). The overall adjusted hazard ratio for any severe, critical, or fatal COVID-19 disease after dose 1 was estimated at 0.71 (95% CI: 0.53-0.95; p=0.020).

Of 443,416 mRNA-1273-vaccinated individuals with no record of prior infection before dose 2, 192,123 were exact-matched to 192,123 BNT162b2-vaccinated individuals with no record of All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint prior infection ( Figure 1 ). These matched cohorts were balanced on the matching factors ( Table   2 ). The median date of dose 2 was May 15, 2021. Among mRNA-1273-and BNT162b2vaccinated individuals, 44.4% and 43.0% had a PCR test done during follow-up, respectively.

Among mRNA-1273-vaccinated individuals, 878 breakthrough infections were recorded after dose 2 at a median follow-up of 89 days (IQR: 29-123 days; Figure 1 ; Table 3 ). Of these infections, 3 progressed to severe COVID-19 disease and none to critical or fatal disease.

Among BNT162b2-vaccinated individuals, 1,262 breakthrough infections were recorded after dose 2 at a median follow-up of 86 days (IQR: 23-122 days; Figure 1 ; Table 3 ). Of these infections, 7 progressed to severe COVID-19 disease, none to critical disease, and 1 to COVID-19 death.

There were minimal differences in median age, age distribution, sex, nationality, and calendar month of dose 2 between mRNA-1273 and BNT162b2 breakthrough infections (Table 3) . Most breakthrough infections in both vaccinated cohorts occurred during the Delta-dominated lowincidence phase after June 2021. 6, 8, 9, 19, [23] [24] [25] The median date of breakthrough infection was July 25, 2021. For both vaccinated cohorts, breakthrough infections tended to occur among those who had received their vaccination earlier ( Figure 2B ).

Cumulative incidence of breakthrough infection after dose 2 was estimated at 0.59% (95% CI: 0.55-0.64%) for mRNA-1273-vaccinated individuals and at 0.84% (95% CI: 0.79-0.89%) for BNT162b2-vaccinated individuals, at 180 days of follow-up ( Figure 2B ). Cumulative incidence curves of the two vaccinated cohorts started to diverge immediately after dose 2, but both curves followed a similar pattern. Cumulative incidence started to plateau around 10 days after dose 2, consistent with attainment of the highest protection against infection after two vaccine doses.

However, at around 90 days after dose 2, both curves started to bend upward, at a time of low All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint infection incidence in the wider population, consistent with progressive waning of vaccine protection.

Breakthrough infection incidence rates among mRNA-1273-and BNT162b2-vaccinated individuals were estimated at 2.25 (95% CI: 2.11-2.41) and 3.25 (95% CI: 3.07-3.43) per 10,000 person-weeks, respectively. The overall hazard ratio for breakthrough infection after dose 2, adjusted for 5-year age group, sex, nationality group, and calendar week of dose 2, was estimated at 0.69 (95% CI: 0.63-0.75; p<0.001). The adjusted hazard ratio was largely stable over time after dose 2 at about this value ( Table 4 ). The overall adjusted hazard ratio for any severe, critical, or fatal COVID-19 disease after dose 2 was estimated at 0.37 (95% CI: 0.10-1.41; p=0.147).

Significant differences were observed in protection offered by the mRNA-1273 vaccine versus that of the BNT162b2 vaccine, against both breakthrough infection and severe COVID-19. These differences started to emerge in the third week after the first dose. Incidence of breakthrough infection in the third week after the first dose, and among persons who received both doses, was 30% lower among mRNA-1273-vaccinated persons compared to that among BNT162b2vaccinated persons. After the first dose, incidence of severe, critical, or fatal COVID-19 cases was 30% lower among mRNA-1273-vaccined persons than among BNT162b2-vaccinated persons. After the second dose, incidence of these cases was also lower among mRNA-1273vaccined persons, but the difference did not reach statistical significance, perhaps because of the small number of cases. The number of severe, critical, or fatal COVID-19 cases was exceedingly small among persons fully vaccinated with either vaccine, indicating robust protection against severe forms of COVID-19.

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The copyright holder for this this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint Despite these differences, both vaccines demonstrated strikingly similar patterns of build-up of protection after the first dose and waning of protection after the second dose. The relative differences between those vaccinated with mRNA-1273 versus BNT162b2 were stable over time after vaccination. For both vaccines, most breakthrough infections after the first dose occurred in the first two weeks after vaccination. Also, for both vaccines, most breakthrough infections after the second dose occurred 90 days or more after the second dose, consistent with similar waning of vaccine immunity for both vaccines. These results may suggest that the nature of immunity that builds after vaccination and wanes over time is similar for both vaccines, but that the differences in the level of protection could be due to differences in the magnitude (not mechanistic type) of initial activation of immune response following the first and second doses.

These findings may be explained by the larger dose of the mRNA-1273 vaccine versus that of the BNT162b2 vaccine. 1, 2 Evidence suggests that the mRNA-1273 vaccine induces higher neutralizing antibody titers than the BNT162b2 vaccine. 4 The interval between first and second doses is one week longer for the mRNA-1273 vaccine, and evidence suggests greater protection with longer interval between doses. 33 This study has the following limitations. Vaccinated cohorts in Qatar predominantly included young and working-age adults; thus, these findings may not generalize to children or older persons. As an observational study, the vaccinated cohorts were neither blinded nor randomized, so the potential for unmeasured or uncontrolled confounding cannot be excluded. While matching was done for age, sex, nationality, and calendar week of the first (or second) vaccine dose, it was not possible for other factors, such as comorbidities or occupation, as these data were not available to study investigators. All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint However, matching was done to control for major factors known to affect risk of exposure to the infection in Qatar, 14,17,26-28 as well as variant exposure over the course of follow-up. 6, 8, 9, 19, [23] [24] [25] Matching by age may have (partially) reduced the potential for bias due to co-morbidities. The number of individuals with severe chronic conditions is also small in Qatar's young population. 14,34 Matching by nationality may have (partially) controlled the differences in occupational risk, in consideration of the association between nationality and occupation in Qatar. 14,17,26-28 Both vaccines were broadly distributed across Qatar's neighborhoods/areas and population social substrata. Individuals were vaccinated by the vaccine that was available at the time of the vaccination appointment. Cohorts were matched by calendar week of the first (or second) dose; thus, vaccination eligibility criteria were the same for both vaccines at the time of vaccination. PCR testing rates were similar for both the mRNA-1273-and BNT162b2vaccinated cohorts. Importantly, there was no difference in infection incidence in the first two weeks after the first dose, as expected, considering evidence of negligible vaccine protection in these two weeks. 1, 2, [6] [7] [8] 19 This supports adequate control of potential bias arising from differences in the risk of exposure to the infection between these vaccinated cohorts.

In conclusion, mRNA-1273 vaccination is associated with significantly lower SARS-CoV-2 breakthrough infection and severe COVID-19 than BNT162b2 vaccination. Despite these differences, both vaccines elicited robust protection against COVID-19 hospitalization and death.

Both vaccines also demonstrated remarkably similar patterns of build-up of protection after the first dose and waning of protection after the second dose. The nature of vaccine immunity that builds after vaccination and wanes over time appears similar for both vaccines. Differences in the level of protection perhaps arise from the differences in the size of the vaccine dose. All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint Programme for institutional support for the reagents needed for the viral genome sequencing.

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the article. Statements made herein are solely the responsibility of the authors.

LJA conceived and co-designed the study, led the statistical analyses, and co-wrote the first draft of the article. HC co-designed the study, performed the statistical analyses, and co-wrote 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.

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The copyright holder for this this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 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. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. ‡ SMD reported here is for the mean difference between groups divided by the pooled standard deviation. § Nationalities were chosen to represent the most numerous groups in the population of Qatar. ¶ There were 164 other nationalities in the full cohort of individuals vaccinated with mRNA-1273, 184 other nationalities in the full cohort of individuals vaccinated with BNT162b2, 115 other nationalities in the matched cohort of individuals vaccinated with mRNA-1273, and 115 other nationalities in the matched cohort of individuals vaccinated with BNT162b2. Abbreviations: IQR, interquartile range; SMD, standardized mean difference. * Cohorts were exact matched in a 1:1 ratio by sex, 5-year age group, nationality, and calendar week of first vaccine dose. † Cohorts were exact matched in a 1:1 ratio by sex, 5-year age group, nationality, and calendar week of second vaccine dose. ‡ SMD is the difference in the mean of a covariate between groups divided by the pooled standard deviation. § SMD reported here is for the mean difference between groups divided by the pooled standard deviation. ¶ Nationalities were chosen to represent the most numerous groups in the population of Qatar.

** There were 34 other nationalities in mRNA-1273-vaccinated individuals with breakthrough infection after dose 1, 51 other nationalities in BNT162b2-vaccinated individual with breakthrough infection after dose 1, 28 other nationalities in mRNA-1273-vaccinated individuals with breakthrough infection after dose 2, and 41 other nationalities in BNT162b2-vaccinated individuals with breakthrough infection after dose 2. † † Calendar month of vaccine dose was for dose 1 in the study assessing breakthrough infections after dose 1, and for dose 2 in the study assessing breakthrough infections after dose 2.

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The copyright holder for this this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint Table 4 All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint COVID-19 severity, criticality, and fatality classification ..................................................... 2   Section 2. Laboratory methods .................................................................................................................. 3 Section 3. Classification of infections by variant type ............................................................................. 4 Table S1 . STROBE checklist for cohort studies. ...................................................................................... 6 References . ................................................................................................................................................... 7 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All PCR testing was conducted at the Hamad Medical Corporation Central Laboratory or Sidra Medicine Laboratory, following standardized protocols.

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The copyright holder for this this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint

Surveillance for SARS-CoV-2 variants in Qatar is based on viral genome sequencing and multiplex, real-time reverse-transcription PCR (RT-qPCR) variant screening 3 All rights reserved. No reuse allowed without permission. preprint (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 this version posted November 13, 2021. ; https://doi.org/10.1101/2021.11.12.21266250 doi: medRxiv preprint All the variant RT-qPCR screening was conducted at the Sidra Medicine Laboratory following standardized protocols.

All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Tables 1-3   Bias  9 Describe any efforts to address potential sources of bias 5 & 7 Study size 10 Explain how the study size was arrived at Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why 7 & Tables 1-3 Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 7 (b) Describe any methods used to examine subgroups and interactions 7 (c) Explain how missing data were addressed NA, see p. 5 (d) If applicable, explain how loss to follow-up was addressed NA (e) Describe any sensitivity analyses NA Results Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed Report numbers of outcome events or summary measures over time 9-10, Figure 1 , Table 3-4  Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included 9-12, Figure 2 , & Table 4 (b) Report category boundaries when continuous variables were categorized Tables 1-3 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period

Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses 10-11 & Table 4 Discussion Key results 18

Summarise key results with reference to study objectives 12-13 Limitations 19

Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence 14 Generalisability 21 Discuss the generalisability (external validity) of the study results 13 Other information Funding 22

Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based

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mRNA-1273 COVID-19 vaccine effectiveness against the B.1.1.7 and B.1.351 variants and severe COVID-19 disease in Qatar

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

We acknowledge the many dedicated individuals at Hamad Medical Corporation, the Ministry of Public Health, the Primary Health Care Corporation, Qatar Biobank, Sidra Medicine, and Weill Cornell Medicine-Qatar for their diligent efforts and contributions to make this study possible.