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BackgroundUnderstanding protection conferred by natural SARS-CoV-2 infection versus COVID-19 vaccination is important for informing vaccine mandate decisions. We compared protection conferred by natural infection versus that from the BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna) vaccines in Qatar. MethodsWe conducted two matched retrospective cohort studies that emulated target trials. Data were obtained from the national federated databases for COVID-19 vaccination, SARS-CoV-2 testing, and COVID-19-related hospitalisation and death between Feb 28, 2020 (pandemic onset in Qatar) and May 12, 2022. We matched individuals with a documented primary infection and no vaccination record (natural infection cohort) with individuals who had received two doses (primary series) of the same vaccine (BNT162b2-vaccinated or mRNA-1273-vaccinated cohorts) at the start of follow-up (90 days after the primary infection). Individuals were exact matched (1:1) by sex, 10-year age group, nationality, comorbidity count, and timing of primary infection or first-dose vaccination. Incidence of SARS-CoV-2 infection and COVID-19-related hospitalisation and death in the natural infection cohorts was compared with incidence in the vaccinated cohorts, using Cox proportional hazards regression models with adjustment for matching factors. FindingsBetween Jan 5, 2021 (date of second-dose vaccine roll-out) and May 12, 2022, 104 500 individuals vaccinated with BNT162b2 and 61 955 individuals vaccinated with mRNA-1273 were matched to unvaccinated individuals with a documented primary infection. During follow-up, 7123 SARS-CoV-2 infections were recorded in the BNT162b2-vaccinated cohort and 3583 reinfections were recorded in the matched natural infection cohort. 4282 SARS-CoV-2 infections were recorded in the mRNA-1273-vaccinated cohort and 2301 reinfections were recorded in the matched natural infection cohort. The overall adjusted hazard ratio (HR) for SARS-CoV-2 infection was 0·47 (95% CI 0·45–0·48) after previous natural infection versus BNT162b2 vaccination, and 0·51 (0·49–0·54) after previous natural infection versus mRNA-1273 vaccination. The overall adjusted HR for severe (acute care hospitalisations), critical (intensive care unit hospitalisations), or fatal COVID-19 cases was 0·24 (0·08–0·72) after previous natural infection versus BNT162b2 vaccination, and 0·24 (0·05–1·19) after previous natural infection versus mRNA-1273 vaccination. Severe, critical, or fatal COVID-19 was rare in both the natural infection and vaccinated cohorts. InterpretationPrevious natural infection was associated with lower incidence of SARS-CoV-2 infection, regardless of the variant, than mRNA primary-series vaccination. Vaccination remains the safest and most optimal tool for protecting against infection and COVID-19-related hospitalisation and death, irrespective of previous infection status. FundingThe Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, Weill Cornell Medicine-Qatar; Qatar Ministry of Public Health; Hamad Medical Corporation; Sidra Medicine; Qatar Genome Programme; and Qatar University Biomedical Research Center. The Biomedical Research Program and the Biostatistics, Epidemiology, and Biomathematics Research Core, Weill Cornell Medicine-Qatar; Qatar Ministry of Public Health; Hamad Medical Corporation; Sidra Medicine; Qatar Genome Programme; and Qatar University Biomedical Research Center.

BackgroundThis study assessed the evolution of COVID-19 severity and fatality by utilizing rigorous and standardized criteria that were consistently applied throughout the pandemic in Qatar.MethodsA national cohort study was conducted on Qataris, using data on COVID-19 acute-care and ICU hospitalizations, as well as severe, critical, and fatal COVID-19 cases classified according to the World Health Organization criteria.ResultsThe cumulative incidence of severe, critical, or fatal COVID-19 after 3.14 years of follow-up was 0.45% (95% CI: 0.43-0.47%). The incidence rate for severe, critical, or fatal COVID-19 throughout the pandemic was 1.43 (95% CI: 1.35-1.50) per 1,000 person-years. In the pre-omicron phase, first omicron wave, and combined phases, it was 2.01 (95% CI: 1.90-2.13), 3.70 (95% CI: 3.25-4.22), and 2.18 (95% CI: 2.07-2.30) per 1,000 person-years, respectively. The post-first omicron phase saw a drastic drop to 0.10 (95% CI: 0.08-0.14) per 1,000 person-years, a 95.4% reduction. Among all severe, critical, and fatal cases, 99.5% occurred during the primary infection. The cumulative incidence of fatal COVID-19 was 0.042% (95% CI: 0.036-0.050%), with an incidence rate of 0.13 (95% CI: 0.11-0.16) per 1,000 person-years. In the post-first omicron phase, the incidence rate of fatal COVID-19 decreased by 90.0% compared to earlier stages. Both severity and fatality exhibited an exponential increase with age and a linear increase with the number of coexisting conditions.ConclusionsThe conclusion of the first omicron wave was a turning point in the severity of the pandemic. While vaccination and enhanced case management reduced severity gradually, the rapid accumulation of natural immunity during the initial omicron wave appears to have played the crucial role in driving this shift in severity.

SummaryBackgroundWaning of natural infection protection and vaccine protection highlight the need to evaluate changes in population immunity over time. Population immunity of previous SARS-CoV-2 infection or of COVID-19 vaccination are defined, respectively, as the overall protection against reinfection or against breakthrough infection at a given point in time in a given population.MethodsWe estimated these population immunities in Qatar’s population between July 1, 2020 and November 30, 2022, to discern generic features of the epidemiology of SARS-CoV-2. Effectiveness of previous infection, mRNA primary-series vaccination, and mRNA booster (third-dose) vaccination in preventing infection were estimated, month by month, using matched, test-negative, case-control studies.FindingsPrevious-infection effectiveness against reinfection was strong before emergence of Omicron, but declined with time after a wave and rebounded after a new wave. Effectiveness dropped immediately after Omicron emergence from 88.3% (95% CI: 84.8-91.0%) in November 2021 to 51.0% (95% CI: 48.3-53.6%) in December 2021. Primary-series effectiveness against infection was 84.0% (95% CI: 83.0-85.0%) in April 2021, soon after introduction of vaccination, before waning gradually to 52.7% (95% CI: 46.5-58.2%) by November of 2021. Effectiveness declined linearly by ∼1 percentage point every 5 days. After Omicron emergence, effectiveness dropped suddenly from 52.7% (95% CI: 46.5-58.2%) in November 2021 to negligible levels in December 2021. Booster effectiveness dropped immediately after Omicron emergence from 83.0% (95% CI: 65.6 -91.6%) in November 2021 to 32.9% (95% CI: 26.7-38.5%) in December 2021, and continued to decline thereafter. Effectiveness of previous infection and vaccination against severe, critical, or fatal COVID-19 were generally >80% throughout the study duration.InterpretationHigh population immunity may not be sustained beyond a year. This creates fertile grounds for repeated waves of infection to occur, but these waves may increasingly exhibit a benign pattern of infection.FundingThe Biomedical Research Program and the Biostatistics, Epidemiology, and the Biomathematics Research Core, both at Weill Cornell Medicine-Qatar, Ministry of Public Health, Hamad Medical Corporation, Sidra Medicine, Qatar Genome Programme, Qatar University Biomedical Research Center, and Qatar University Internal Grant ID QUCG-CAS-23/24-114.Research in contextEvidence before this studySARS-CoV-2 infection induces protection against reinfection, but this protection wanes with time since last infection. Similarly, COVID-19 primary-series and booster vaccination induce protection against SARS-CoV-2 infection, but this protection also wanes with time since last dose. These immunity patterns demonstrate the need for the concept ofpopulation immunityto track evolution of overall immune protection over time in a given population. Previous-infection and vaccine population immunities in a specific country can be defined as the overall protection against infection at a given point in time in the full national population. A search of PubMed, Google Scholar, and the International Vaccine Access Center’s VIEW-hub databases up to April 21, 2023 using the keywords “vaccination”, “infection”, “immunity”, “protection”, “SARS-CoV-2”, and “COVID-19” did not identify studies that investigated this epidemiological concept for a national population throughout the COVID-19 pandemic.Added value of this studyThis study analyzed the national federated databases for SARS-CoV-2 infection and COVID-19 vaccination in Qatar, a country that experienced SARS-CoV-2 waves dominated by different pre-Omicron variants and Omicron subvariants. Using a matched, test-negative study design, population immunity against infection of each of previous infection, primary-series vaccination, and booster vaccination were characterized at the national level month by month for two calendar years to discern generic features of the epidemiology of SARS-CoV-2. The three forms of population immunity showed rapid variation over time driven by waning of protection. Vaccine-derived population immunity declined by 1 absolute percentage point every 5 days. Omicron introduction immensely reduced the three forms of population immunity within one month by about 50 absolute percentage points. Meanwhile, previous-infection and vaccine population immunities against severe COVID-19 were durable with slow waning even after Omicron emergence.Implications of all available evidenceBoth previous-infection and vaccine population immunities vary rapidly at a national level creating fertile grounds for repeated waves of infection to occur even within months of each other. High levels of population immunity may not be sustained for more than a year or so. Preventing infection/reinfection, transmission, or future waves of infection cannot sustainably be done with current vaccines nor by the entire population being infected. Timely administration of boosters for those vulnerable to severe COVID-19 may remain essential for years to come. Repeated waves of infection may also facilitate further evolution of the virus and continual immune evasion. Emergence of a new variant that is substantially different from circulating variants can suddenly and immensely reduce population immunity leading to large epidemic waves. However, the durability of population immunity against severe COVID-19 will likely curtail the severity of future waves.

BackgroundProtection against SARS-CoV-2 symptomatic infection and severe COVID-19 of previous infection, mRNA two-dose vaccination, mRNA three-dose vaccination, and hybrid immunity of previous infection and vaccination were investigated in Qatar for the Alpha, Beta, and Delta variants.MethodsSix national, matched, test-negative, case-control studies were conducted between January 18-December 18, 2021 on a sample of 239,120 PCR-positive tests and 6,103,365 PCR-negative tests.ResultsEffectiveness of previous infection against Alpha, Beta, and Delta reinfection was 89.5% (95% CI: 85.5-92.3%), 87.9% (95% CI: 85.4-89.9%), and 90.0% (95% CI: 86.7-92.5%), respectively. Effectiveness of two-dose BNT162b2 vaccination against Alpha, Beta, and Delta infection was 90.5% (95% CI, 83.9-94.4%), 80.5% (95% CI: 79.0-82.0%), and 58.1% (95% CI: 54.6-61.3%), respectively. Effectiveness of three-dose BNT162b2 vaccination against Delta infection was 91.7% (95% CI: 87.1-94.7%). Effectiveness of hybrid immunity of previous infection and two-dose BNT162b2 vaccination was 97.4% (95% CI: 95.4-98.5%) against Beta infection and 94.5% (95% CI: 92.8-95.8%) against Delta infection. Effectiveness of previous infection and three-dose BNT162b2 vaccination was 98.1% (95% CI: 85.7-99.7%) against Delta infection. All five forms of immunity had >90% protection against severe, critical, or fatal COVID-19 regardless of variant. Similar effectiveness estimates were observed for mRNA-1273.ConclusionsAll forms of natural and vaccine immunity prior to Omicron introduction provided strong protection against infection and severe COVID-19. Hybrid immunity conferred the strongest protection and its level was consistent with previous-infection immunity and vaccine immunity acting independently of each other.

BackgroundRisk of short- and long-term all-cause mortality after a primary SARS-CoV-2 infection is inadequately understood.MethodsA national, matched, retrospective cohort study was conducted in Qatar to assess the risk of all-cause mortality in the national cohort of people infected with SARS-CoV-2 compared with a reference national control cohort of uninfected persons. Associations were estimated using Cox proportional-hazards regression models.ResultsAmong unvaccinated persons, within 90 days after primary infection, adjusted hazard ratio (aHR) comparing incidence of death in the primary-infection cohort with the infection-naïve cohort was 1.19 (95% CI: 1.02-1.39). The aHR was 1.34 (95% CI: 1.11-1.63) in persons more clinically vulnerable to severe COVID-19 and 0.94 (95% CI: 0.72-1.24) in those less clinically vulnerable to severe COVID-19. In subsequent follow-up, the aHR was 0.50 (95% CI: 0.37-0.68). The aHR was 0.41 (95% CI: 0.28-0.58) in months 3-7 after the primary infection and 0.76 (95% CI: 0.46-1.26) in subsequent months. The aHR was 0.37 (95% CI: 0.25-0.54) in persons more clinically vulnerable to severe COVID-19 and 0.77 (95% CI: 0.48-1.24) in those less clinically vulnerable to severe COVID-19. Among vaccinated persons, no evidence was found for differences in incidence of death in the primary-infection versus infection-naïve cohorts, even among persons more clinically vulnerable to severe COVID-19.ConclusionsCOVID-19 mortality in Qatar appears primarily driven by forward displacement of deaths of individuals with relatively short life expectancy and more clinically vulnerable to severe COVID-19. Vaccination negated the mortality displacement by preventing early deaths.

BackgroundCoronavirus Disease 2019 (COVID-19) vaccine antigen dosage may affect protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but direct evidence to quantify this effect is lacking.MethodsA matched, retrospective, cohort study that emulated a randomized control trial was conducted in Qatar between February 3, 2022 and November 8, 2022, to provide a head-to-head, controlled comparison of protection induced by two antigen dosages of the BNT162b2 vaccine. The study compared incidence of omicron infection in the national cohort of adolescents 12 years of age who received the two-dose primary-series of the 30-µg BNT162b2 vaccine to that in the national cohort of adolescents 11 years of age who received the two-dose primary-series of the pediatric 10-µg BNT162b2 vaccine. Associations were estimated using Cox proportional-hazard regression models.ResultsAmong adolescents with no record of prior infection, cumulative incidence of infection was 6.0% (95% CI: 4.9-7.3%) for the 30-µg cohort and 7.2% (95% CI: 6.1-8.5%) for the 10-µg cohort, 210 days after the start of follow-up. Incidence during follow-up was dominated by omicron subvariants including, consecutively, BA.1/BA.2, BA.4/BA.5, BA.2.75*, and XBB. The adjusted hazard ratio comparing incidence of infection in the 30-µg cohort to the 10-µg cohort was 0.77 (95% CI: 0.60-0.98). Corresponding relative effectiveness was 23.4% (95% CI: 1.6-40.4%). Relative effectiveness was -3.3% (95% CI: -68.0-27.5%) among adolescents with a record of prior infection.ConclusionsThree-fold higher BNT162b2 dosage was associated with ∼25% higher protection against infection in infection-naïve adolescents of similar age. These findings may inform design of future COVID-19 vaccines and boosters for persons of different age groups.

Background Protection offered by five different forms of immunity, combining natural and vaccine immunity, was investigated against symptomatic SARS-CoV-2 infection from Omicron BA.1 or BA.2, and severe, critical, or fatal COVID-19 from BA.1 or BA.2, in Qatar, between December 23, 2021 and February 21, 2022. Methods Six national, matched, test-negative case-control studies were conducted on a sample of 272,861 PCR-positive tests and 669,628 PCR-negative tests to estimate effectiveness of BNT162b2 (Pfizer-BioNTech) vaccine, mRNA-1273 (Moderna) vaccine, natural immunity due to prior infection with pre-Omicron variants, and hybrid immunity from prior infection and vaccination. Results Effectiveness of prior infection alone against symptomatic BA.2 infection was 46.1% (95% CI: 39.5-51.9%). Effectiveness of two-dose BNT162b2 vaccination alone was negligible at -1.1% (95% CI: -7.1-4.6), but nearly all individuals received their second dose >6 months earlier. Effectiveness of three-dose BNT162b2 vaccination alone was 52.2% (95% CI: 48.1-55.9%). Effectiveness of hybrid immunity of prior infection and two-dose BNT162b2 vaccination was 55.1% (95% CI: 50.9-58.9%). Effectiveness of hybrid immunity of prior infection and three-dose BNT162b2 vaccination was 77.3% (95% CI: 72.4-81.4%). Meanwhile, prior infection, BNT162b2 vaccination, and hybrid immunity all showed strong effectiveness ( >70%) against severe, critical, or fatal COVID-19 due to BA.2. Similar patterns of effectiveness were observed for BA.1 and for the mRNA-1273 vaccine. Figure 1.Effectiveness of prior infection, vaccination, and hybrid immunity against symptomatic Omicron infection and against severe, critical, or fatal COVID-19 for the BA.1 (panels A and B, respectively) and BA.2 (panels C and D, respectively) subvariants in the BNT162b2-vaccine study.Figure 2.Effectiveness of prior infection, vaccination, and hybrid immunity against symptomatic Omicron infection and against severe, critical, or fatal COVID-19 for the BA.1 (panels A and B, respectively) and BA.2 (panels C and D, respectively) subvariants in the mRNA-1273-vaccine study. Conclusion There are no discernable differences between BA.1 and BA.2 in the effects of prior infection, vaccination, and hybrid immunity. Vaccination enhances the protection of those with a prior infection. Hybrid immunity resulting from prior infection and recent booster vaccination conferred the strongest protection. Disclosures Adeel A. Butt, MBBS, Gilead Sciences: Grant/Research Support.

Background: Breakthrough infections after SARS-CoV-2 vaccination have been reported. Clinical outcomes in these persons are not widely known. Methods: We evaluated all vaccinated persons with breakthrough infection ≥14 days after the second vaccine dose and unvaccinated controls matched on age, sex, nationality, and reason for testing between December 23, 2020 and March 28, 2021 in Qatar. Our primary outcome was severe disease defined as hospitalization, mechanical ventilation, or death. Results: Among 456 persons cases of breakthrough infection and 456 unvaccinated matched controls with confirmed infection, median age was 45 years, 60.7% were males, and ≥1 comorbid condition was present in 61.2% of the vaccinated and 47.8% of the unvaccinated persons (P=0.009). Severe disease was recorded in 48 (10.5%) of the vaccinated and 121 (26.5%) of the unvaccinated group (P40–60 years, HR 2.32; >60–70 years, HR 4.34; >70 years, HR 5.43); presence of symptoms at baseline (HR 2.42, 95%CI 1.44-4.07); and being unvaccinated (HR 2.84, 95%CI 1.80-4.47). Conclusions: In persons with breakthrough SARS-CoV-2 infection, increasing age is associated with a higher risk of severe disease or death, while vaccination is associated with a lower risk. Presence of comorbidities was not associated with severe disease or death among persons with breakthrough infection.

BackgroundLong-term effectiveness of COVID-19 mRNA boosters in populations with different prior infection histories and clinical vulnerability profiles is inadequately understood.MethodsA national, matched, retrospective, target trial cohort study was conducted in Qatar to investigate effectiveness of a third mRNA (booster) dose, relative to a primary series of two doses, against SARS-CoV-2 omicron infection and against severe COVID-19. Associations were estimated using Cox proportional-hazards regression models.ResultsBooster effectiveness relative to primary series was 41.1% (95% CI: 40.0-42.1%) against infection and 80.5% (95% CI: 55.7-91.4%) against severe, critical, or fatal COVID-19, over one-year follow-up after the booster. Among persons clinically vulnerable to severe COVID-19, effectiveness was 49.7% (95% CI: 47.8-51.6%) against infection and 84.2% (95% CI: 58.8-93.9%) against severe, critical, or fatal COVID-19. Effectiveness against infection was highest at 57.1% (95% CI: 55.9-58.3%) in the first month after the booster but waned thereafter and was modest at only 14.4% (95% CI: 7.3-20.9%) by the sixth month. In the seventh month and thereafter, coincident with BA.4/BA.5 and BA.2.75* subvariant incidence, effectiveness was progressively negative reaching -20.3% (95% CI: -55.0-29.0%) after one year of follow-up. Similar levels and patterns of protection were observed irrespective of prior infection status, clinical vulnerability, or type of vaccine (BNT162b2 versus mRNA-1273).ConclusionsBoosters reduced infection and severe COVID-19, particularly among those clinically vulnerable to severe COVID-19. However, protection against infection waned after the booster, and eventually suggested an imprinting effect of compromised protection relative to the primary series. However, imprinting effects are unlikely to negate the overall public health value of booster vaccinations.

Background The future of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic hinges on virus evolution and duration of immune protection of natural infection against reinfection. We investigated the duration of protection afforded by natural infection, the effect of viral immune evasion on duration of protection and protection against severe reinfection, in Qatar, between 28 February 2020 and 5 June 2022. Methods Three national, matched, retrospective cohort studies were conducted to compare the incidence of SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) severity among unvaccinated persons with a documented SARS-CoV-2 primary infection, to incidence among those infection-naïve and unvaccinated. Associations were estimated using Cox proportional hazard regression models. Results Effectiveness of pre-Omicron primary infection against pre-Omicron reinfection was 85.5% [95% confidence interval (CI): 84.8–86.2%]. Effectiveness peaked at 90.5% (95% CI: 88.4–92.3%) in the 7th month after the primary infection, but waned to ~ 70% by the 16th month. Extrapolating this waning trend using a Gompertz curve suggested an effectiveness of 50% in the 22nd month and Conclusions Protection of natural infection against reinfection wanes and may diminish within a few years. Viral immune evasion accelerates this waning. Protection against severe reinfection remains very strong, with no evidence for waning, irrespective of variant, for over 14 months after primary infection.

BackgroundThe BNT162b2 COVID-19 vaccine is authorized for children 5-11 years of age and adolescents 12-17 years of age, but in different dose sizes. We assessed BNT162b2 real-world effectiveness against SARS-CoV-2 infection among children and adolescents in Qatar.MethodsThree matched, retrospective, target-trial, cohort studies were conducted to compare incidence of SARS-CoV-2 infection in the national cohort of vaccinated individuals to incidence in the national cohort of unvaccinated individuals. Associations were estimated using Cox proportional-hazards regression models.ResultsEffectiveness of the 10 µg dose for children against Omicron infection was 25.7% (95% CI: 10.0-38.6%). It was highest at 49.6% (95% CI: 28.5-64.5%) right after the second dose, but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI: 21.5-63.3%) among those aged 5-7 years and 16.6% (−4.2-33.2%) among those aged 8-11 years. Effectiveness of the 30 µg dose for adolescents against Omicron infection was 30.6% (95% CI: 26.9-34.1%), but many adolescents were vaccinated months earlier. Effectiveness waned with time after the second dose. Effectiveness was 35.6% (95% CI: 31.2-39.6%) among those aged 12-14 years and 20.9% (13.8-27.4%) among those aged 15-17 years. Effectiveness of the 30 µg dose for adolescents against pre-Omicron infection was 87.6% (95% CI: 84.0-90.4%) and waned relatively slowly after the second dose.ConclusionsPediatric vaccination is associated with modest and rapidly waning protection against Omicron infection. Adolescent vaccination is associated with stronger and more durable protection, perhaps because of the larger dose size. Age at such young age appears to play a role in determining vaccine protection, with greater protection observed in younger than older children or adolescents.

BACKGROUNDThe future of the SARS-CoV-2 pandemic hinges on virus evolution and duration of immune protection of natural infection against reinfection. We investigated duration of protection afforded by natural infection, the effect of viral immune evasion on duration of protection, and protection against severe reinfection, in Qatar, between February 28, 2020 and June 5, 2022.METHODSThree national, matched, retrospective cohort studies were conducted to compare incidence of SARS-CoV-2 infection and COVID-19 severity among unvaccinated persons with a documented SARS-CoV-2 primary infection, to incidence among those infection-naïve and unvaccinated. Associations were estimated using Cox proportional-hazard regression models.RESULTSEffectiveness of pre-Omicron primary infection against pre-Omicron reinfection was 85.5% (95% CI: 84.8-86.2%). Effectiveness peaked at 90.5% (95% CI: 88.4-92.3%) in the 7th month after the primary infection, but waned to ∼70% by the 16th month. Extrapolating this waning trend using a Gompertz curve suggested an effectiveness of 50% in the 22nd month and nd month. Effectiveness of pre-Omicron primary infection against Omicron reinfection was 38.1% (95% CI: 36.3-39.8%) and declined with time since primary infection. A Gompertz curve suggested an effectiveness of th month. Effectiveness of primary infection against severe, critical, or fatal COVID-19 reinfection was 97.3% (95% CI: 94.9- 98.6%), irrespective of the variant of primary infection or reinfection, and with no evidence for waning. Similar results were found in sub-group analyses for those ≥50 years of age.CONCLUSIONSProtection of natural infection against reinfection wanes and may diminish within a few years. Viral immune evasion accelerates this waning. Protection against severe reinfection remains very strong, with no evidence for waning, irrespective of variant, for over 14 months after primary infection.

Understanding the disease severity associated with the Omicron variant of the SARS-CoV-2 virus is important in determining appropriate management strategies at the individual and population levels. We determined the severity of SARS-CoV-2 infection in persons infected with the Omicron vs the Delta variant.We identified individuals with SARS-CoV-2 infection with Delta and propensity-score matched controls with Omicron variant infection from the National COVID-19 Database in Qatar. We excluded temporary visitors to Qatar, those with a prior documented infection, those ≤18 years old, and those with14 days of follow up after the index test positive date. We determined the rates of admission to the hospital, admission to intensive care unit, mechanical ventilation, or death among those infected with the Delta or Omicron variants.Among 9763 cases infected with the Delta variant and 11 310 cases infected with the Omicron variant, we identified 3926 propensity-score matched pairs. Among 3926 Delta infected, 3259 (83.0%) had mild, 633 (16.1%) had moderate and 34 (0.9%) had severe/critical disease. Among 3926 Omicron infected, 3866 (98.5%) had mild, 59 (1.5%) had moderate, and only 1 had severe/critical disease (overall P 0.001). Factors associated with less moderate or severe/critical disease included infection with Omicron variant (aOR = 0.06; confidence interval (CI) = 0.05-0.09) and vaccination including a booster (aOR = 0.30; 95% CI = 0.09-0.99).Omicron variant infection is associated with significantly lower severity of disease compared with the Delta variant. Vaccination continues to offer strong protection against severe/critical disease.

We investigated what proportion of the population acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and whether the herd immunity threshold has been reached in 10 communities in Qatar. The study included 4,970 participants during June 21–September 9, 2020. Antibodies against SARS-CoV-2 were detected by using an electrochemiluminescence immunoassay. Seropositivity ranged from 54.9% (95% CI 50.2%–59.4%) to 83.8% (95% CI 79.1%–87.7%) across communities and showed a pooled mean of 66.1% (95% CI 61.5%–70.6%). A range of other epidemiologic measures indicated that active infection is rare, with limited if any sustainable infection transmission for clusters to occur. Only 5 infections were ever severe and 1 was critical in these young communities; infection severity rate of 0.2% (95% CI 0.1%–0.4%). Specific communities in Qatar have or nearly reached herd immunity for SARS-CoV-2 infection: 65%–70% of the population has been infected.

ObjectiveTo investigate all-cause mortality, COVID-19 mortality and all-cause non-COVID-19 mortality in Qatar during the COVID-19 pandemic.MethodsA national, retrospective cohort analysis and national, matched, retrospective cohort studies were conducted between 5 February 2020 and 19 September 2022.ResultsThere were 5025 deaths during a follow-up time of 5 247 220 person-years, of which 675 were COVID-19 related. Incidence rates were 0.96 (95% CI 0.93 to 0.98) per 1000 person-years for all-cause mortality, 0.13 (95% CI 0.12 to 0.14) per 1000 person-years for COVID-19 mortality and 0.83 (95% CI 0.80 to 0.85) per 1000 person-years for all-cause non-COVID-19 mortality. Adjusted HR, comparing all-cause non-COVID-19 mortality relative to Qataris, was lowest for Indians at 0.38 (95% CI 0.32 to 0.44), highest for Filipinos at 0.56 (95% CI 0.45 to 0.69) and was 0.51 (95% CI 0.45 to 0.58) for craft and manual workers (CMWs). Adjusted HR, comparing COVID-19 mortality relative to Qataris, was lowest for Indians at 1.54 (95% CI 0.97 to 2.44), highest for Nepalese at 5.34 (95% CI 1.56 to 18.34) and was 1.86 (95% CI 1.32 to 2.60) for CMWs. Incidence rate of all-cause mortality for each nationality group was lower than the crude death rate in the country of origin.ConclusionsRisk of non-COVID-19 death was low and was lowest among CMWs, perhaps reflecting the healthy worker effect. Risk of COVID-19 death was also low, but was highest among CMWs, largely reflecting higher exposure during first epidemic wave, before advent of effective COVID-19 treatments and vaccines.

BACKGROUNDQatar experienced a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021 and peaked in mid-January, 2022. We investigated effects of Omicron subvariant (BA.1 and BA.2), previous vaccination, and prior infection on infectiousness of Omicron infections, between December 23, 2021 and February 20, 2022.METHODSUnivariable and multivariable regression analyses were conducted to estimate the association between the RT-qPCR cycle threshold (Ct) value of PCR tests (a proxy for SARS-CoV-2 infectiousness) and each of the Omicron subvariants, mRNA vaccination, prior infection, reason for RT-qPCR testing, calendar week of RT-qPCR testing (to account for phases of the rapidly evolving Omicron wave), and demographic factors.RESULTSCompared to BA.1, BA.2 was associated with 3.53 fewer cycles (95% CI: 3.46-3.60), signifying higher infectiousness. Ct value decreased with time since second and third vaccinations. Ct values were highest for those who received their boosters in the month preceding the RT-qPCR test—0.86 cycles (95% CI: 0.72-1.00) higher than for unvaccinated persons. Ct value was 1.30 (95% CI: 1.20-1.39) cycles higher for those with a prior infection compared to those without prior infection, signifying lower infectiousness. Ct value declined gradually with age. Ct value was lowest for those who were tested because of symptoms and was highest for those who were tested for travel-related purposes. Ct value was lowest during the exponential-growth phase of the Omicron wave and was highest after the wave peaked and was declining.CONCLUSIONSThe BA.2 subvariant appears substantially more infectious than the BA.1 subvariant. This may reflect higher viral load and/or longer duration of infection, thereby explaining the rapid expansion of this subvariant in Qatar.

Introduction. The cycle threshold (Ct) value in real-time PCR (RT-PCR) is where a target-specific amplification signal becomes detectable and can infer viral load, risk of transmission and recovery. Use of Ct values in routine practice is uncommon. Gap Statement. There is a lack of routine use of Ct values when reporting RT-PCR results in routine practice. Aim. To automatically insert Ct values and interpretive comments when reporting SARS-CoV-2 RT-PCR to improve patient management. Methodology. Routine Ct values across three different RT-PCR platforms were reviewed for concordance at presentation and clearance in patients with COVID-19. An indicative threshold (IT) linked to viral clearance kinetics was defined at Ct30 to categorize Ct values as low and high, reflecting high and low viral loads respectively. Results. The different gene targets of each platform showed high correlation and kappa score agreement (PCt30 as reactive; interpretive comments were added to all reports. The new reporting algorithm impacted on: physician interpretation of SARS-CoV-2 results; patient management and transfer; staff surveillance; length of stay in quarantine; and redefinition of patient recovery. Conclusion. Incorporation of Ct values into routine practice is possible across different RT-PCR platforms and adds useful information for patient management. The use of an IT with interpretive comments improves clinical interpretation and could be a model for reporting other respiratory infections. Withholding Ct values wastes useful clinical data and should be reviewed by the profession, accreditation bodies and regulators.

BACKGROUND: Protection offered by five different forms of immunity, combining natural and vaccine immunity, was investigated against SARS-CoV-2 Omicron symptomatic BA.1 infection, symptomatic BA.2 infection, BA.1 hospitalization and death, and BA.2 hospitalization and death, in Qatar, between December 23, 2021 and February 21, 2022. METHODS: Six national, matched, test-negative case-control studies were conducted to estimate effectiveness of BNT162b2 (Pfizer-BioNTech) vaccine, mRNA-1273 (Moderna) vaccine, natural immunity due to prior infection with pre-Omicron variants, and hybrid immunity from prior infection and vaccination. RESULTS: Effectiveness of only prior infection against symptomatic BA.2 infection was 46.1% (95% CI: 39.5-51.9%). Effectiveness of only two-dose BNT162b2 vaccination was negligible at -1.1% (95% CI: -7.1-4.6), but nearly all individuals had received their second dose several months earlier. Effectiveness of only three-dose BNT162b2 vaccination was 52.2% (95% CI: 48.1-55.9%). Effectiveness of hybrid immunity of prior infection and two-dose BNT162b2 vaccination was 55.1% (95% CI: 50.9-58.9%). Effectiveness of hybrid immunity of prior infection and three-dose BNT162b2 vaccination was 77.3% (95% CI: 72.4-81.4%). Meanwhile, prior infection, BNT162b2 vaccination, and hybrid immunity all showed strong effectiveness >70% against any severe, critical, or fatal COVID-19 due to BA.2 infection. Similar levels and patterns of effectiveness were observed for BA.1 and for the mRNA-1273 vaccine. CONCLUSIONS: There are no discernable differences in the effects of prior infection, vaccination, and hybrid immunity against BA.1 versus BA.2. Hybrid immunity resulting from prior infection and recent booster vaccination confers the strongest protection against either subvariant. Vaccination enhances protection of those with a prior infection.

BACKGROUNDProtection conferred by natural SARS-CoV-2 infection versus COVID-19 vaccination has not been investigated in rigorously controlled studies. We compared head-to-head protection conferred by natural infection to that from the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines in Qatar, between February 28, 2020 and March 6, 2022.METHODSTwo national matched retrospective target-trial cohort studies were conducted to compare incidence of SARS-CoV-2 infection and COVID-19 hospitalization and death among those with a documented primary infection to incidence among those with a two-dose primary-series vaccination. Associations were estimated using Cox proportional-hazards regression models.RESULTSThe overall adjusted hazard ratio (AHR) for infection was 0.46 (95% CI: 0.45-0.48) comparing those with a prior infection to those vaccinated with BNT162b2, and 0.51 (95% CI: 0.48-0.53) comparing those with a prior infection to those vaccinated with mRNA-1273. For BNT162b2, the AHR decreased gradually from 0.55 (95% CI: 0.46-0.65) in the fourth month after primary infection/vaccination to 0.31 (95% CI: 0.27-0.37) in the eighth month, while for mRNA-1273, it decreased from 0.80 (95% CI: 0.59-1.07) to 0.35 (95% CI: 0.29-0.41) over the same time period. During the Omicron wave, the AHR was ∼0.50 for BNT162b2 and ∼0.60 for mRNA-1273. The overall AHR for any severe, critical, or fatal COVID-19 (against all variants) was 0.32 (95% CI: 0.10-1.00) for BNT162b2, and 0.58 (95% CI: 0.14-2.43) for mRNA-1273.CONCLUSIONSNatural infection was associated with stronger and more durable protection against infection, regardless of the variant, than mRNA primary-series vaccination. Nonetheless, vaccination remains the safest and optimal tool of protection against infection and COVID-19 hospitalization and death.

BackgroundThe effective reproduction number,Rt, is a tool to track and understand epidemic dynamics. This investigation ofRtestimations was conducted to guide the national COVID-19 response in Qatar, from the onset of the epidemic until August 18, 2021.MethodsReal-time “empirical”was estimated using five methods, including the Robert Koch Institute, Cislaghi, Systrom-Bettencourt and Ribeiro, Wallinga and Teunis, and Cori et al. methods.Rwas also estimated using a transmission dynamics model. Uncertainty and sensitivity analyses were conducted. Agreements between differentRtestimates were assessed by calculating correlation coefficients.Resultscaptured the evolution of the epidemic through three waves, public health response landmarks, effects of major social events, transient fluctuations coinciding with significant clusters of infection, and introduction and expansion of the B.1.1.7 variant. The various estimation methods produced consistent and overall comparableestimates with generally large correlation coefficients. The Wallinga and Teunis method was the fastest at detecting changes in epidemic dynamics.estimates were consistent whether using time series of symptomatic PCR-confirmed cases, all PCR-confirmed cases, acute-care hospital admissions, or ICU-care hospital admissions, to proxy trends in true infection incidence.correlated strongly withand provided an average.ConclusionsRtestimations were robust and generated consistent results regardless of the data source or the method of estimation. Findings affirmed an influential role forRtestimations in guiding national responses to the COVID-19 pandemic, even in resource-limited settings.

BACKGROUNDQatar has been experiencing a large SARS-CoV-2 Omicron (B.1.1.529) wave that started on December 19, 2021. We assessed duration of protection of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines after second dose and after third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021 and February 2, 2022.METHODSVaccine effectiveness was estimated using the test-negative, case-control study design, applying the same methodology used earlier to assess waning of BNT162b2 and mRNA-1273 effectiveness in the same population during earlier infection waves.RESULTSBNT162b2 effectiveness against symptomatic Omicron infection was highest at 61.9% (95% CI: 49.9-71.1%) in the first month after the second dose, but then gradually declined and was at 10% or less starting from the 5th month after the second dose. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then started to decline again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was maintained at >70% after the second dose and at >90% after the booster with no evidence for declining effectiveness over time. mRNA-1273 effectiveness against symptomatic Omicron infection was highest at 44.8% (95% CI: 16.0-63.8%) in the first three months after the second dose, before gradually declining to negligible levels thereafter. After the booster, effectiveness rapidly rebounded to peak at about 55% between 2-5 weeks after the booster, but then declined again thereafter. Effectiveness against severe, critical, or fatal COVID-19 was high at >60% after the second dose and at >80% after the booster, but the confidence intervals were wide owing to the small number of cases.CONCLUSIONSBNT162b2 and mRNA-1273 vaccines show a similar level and pattern of protection against symptomatic Omicron infection. Protection against Omicron is lower than that against Alpha, Beta, and Delta variants, and wanes more rapidly than against earlier variants after the second and booster doses. Meanwhile, protection against hospitalization and death appears robust and durable after both the second and booster doses.

BACKGROUNDWaning of COVID-19 vaccine protection and emergence of SARS-CoV-2 Omicron (B.1.1.529) variant have expedited efforts to scale up booster vaccination. This study compared protection afforded by booster doses of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines, compared to the primary series of only two doses in Qatar, during a large, rapidly growing Omicron wave.METHODSIn a population of 2,232,224 vaccinated persons with at least two doses, two matched, retrospective cohort studies were implemented to investigate effectiveness of booster vaccination against symptomatic SARS-CoV-2 infection and against COVID-19 hospitalization and death, up to January 9, 2022. Association of booster status with infection was estimated using Cox proportional-hazards regression models.RESULTSFor BNT162b2, cumulative symptomatic infection incidence was 2.9% (95% CI: 2.8-3.1%) in the booster-dose cohort and 5.5% (95% CI: 5.3-5.7%) in the primary-series cohort, after 49 days of follow-up. Adjusted hazard ratio for symptomatic infection was 0.50 (95% CI: 0.47-0.53). Booster effectiveness relative to primary series was 50.1% (95% CI: 47.3-52.8%). For mRNA-1273, cumulative symptomatic infection incidence was 1.9% (95% CI: 1.7-2.2%) in the booster-dose cohort and 3.5% (95% CI: 3.2-3.9%) in the primary-series cohort, after 35 days of follow-up. The adjusted hazard ratio for symptomatic infection was 0.49 (95% CI: 0.43-0.57). Booster effectiveness relative to primary series was 50.8% (95% CI: 43.4-57.3%). There were fewer cases of severe COVID-19 in booster-dose cohorts than in primary-series cohorts, but cases of severe COVID-19 were rare in all cohorts.CONCLUSIONSmRNA booster vaccination is associated with modest effectiveness against symptomatic infection with Omicron. The development of a new generation of vaccines targeting a broad range of variants may be warranted.

BACKGROUNDNatural 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.METHODSPES 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.RESULTSPES 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.CONCLUSIONSProtection 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.

BackgroundThe Coronavirus Disease 2019 (COVID-19) pandemic has highlighted an urgent need to use infection testing databases to rapidly estimate effectiveness of prior infection in preventing reinfection (PES) by novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).MethodsMathematical modeling was used to demonstrate the applicability of the test-negative, case-control study design to derive PES. Modeling was also used to investigate effects of bias in PES estimation. The test-negative design was applied to national-level testing data in Qatar to estimate PES for SARS-CoV-2 infection and to validate this design.ResultsApart from the very early phase of an epidemic, the difference between the test-negative estimate for PES and the true value of PES was minimal and became negligible as the epidemic progressed. The test-negative design provided robust estimation of PES even when PES began to wane after prior infection. Assuming that only 25% of prior infections are documented, misclassification of prior infection status underestimated PES, but the underestimate was considerable only when >50% of the population was ever infected. Misclassification of latent infection, misclassification of current active infection, and scale-up of vaccination all resulted in negligible bias in estimated PES. PES against SARS-CoV-2 Alpha and Beta variants was estimated at 97.0% (95% CI: 93.6-98.6) and 85.5% (95% CI: 82.4-88.1), respectively. These estimates were validated using a cohort study design.ConclusionsThe test-negative design offers a feasible, robust method to estimate protection from prior infection in preventing reinfection.