All-cause and COVID-19 mortality in Qatar during the COVID-19 pandemic.

OBJECTIVE: To investigate all-cause mortality, COVID-19 mortality and all-cause non-COVID-19 mortality in Qatar during the COVID-19 pandemic. METHODS: A national, retrospective cohort analysis and national, matched, retrospective cohort studies were conducted between 5 February 2020 and 19 September 2022. RESULTS: There 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. CONCLUSIONS: Risk 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.

Effects of SARS-CoV-2 Alpha, Beta, and Delta variants, age, vaccination, and prior infection on infectiousness of SARS-CoV-2 infections.

In 2021, Qatar experienced considerable incidence of SARS-CoV-2 infection that was dominated sequentially by the Alpha, Beta, and Delta variants. Using the cycle threshold (Ct) value of an RT-qPCR-positive test to proxy the inverse of infectiousness, we investigated infectiousness of SARS-CoV-2 infections by variant, age, sex, vaccination status, prior infection status, and reason for testing in a random sample of 18,355 RT-qPCR-genotyped infections. Regression analyses were conducted to estimate associations with the Ct value of RT-qPCR-positive tests. Compared to Beta infections, Alpha and Delta infections demonstrated 2.56 higher Ct cycles (95% CI: 2.35-2.78), and 4.92 fewer cycles (95% CI: 4.67- 5.16), respectively. The Ct value declined gradually with age and was especially high for children <10 years of age, signifying lower infectiousness in small children. Children <10 years of age had 2.18 higher Ct cycles (95% CI: 1.88-2.48) than those 10-19 years of age. Compared to unvaccinated individuals, the Ct value was higher among individuals who had received one or two vaccine doses, but the Ct value decreased gradually with time since the second-dose vaccination. Ct value was 2.07 cycles higher (95% CI: 1.42-2.72) for those with a prior infection than those without prior infection. The Ct value was lowest among individuals tested because of symptoms and was highest among individuals tested as a travel requirement. Delta was substantially more infectious than Beta. Prior immunity, whether due to vaccination or prior infection, is associated with lower infectiousness of breakthrough infections, but infectiousness increases gradually with time since the second-dose vaccination.

Immediate and contributory causes of death in patients hospitalized with COVID-19.

OBJECTIVES: Accurate determination of the immediate causes of death in patients with COVID-19 is important for optimal care and mitigation strategies. METHODS: All deaths in Qatar between March 01, 2020, and August 31, 2022, flagged for likely relationship to COVID-19 were reviewed by two independent, trained reviewers using a standardized methodology to determine the immediate and contributory causes of death. RESULTS: Among 749 flagged deaths, the most common admitting diagnoses were respiratory tract infection (91%) and major adverse cardiac event (MACE, 2.3%). The most common immediate causes of death were COVID-19 pneumonia (66.2%), MACE (7.1%), hospital-associated pneumonia (HAP, 6.8%), bacteremia (6.3%), disseminated fungal infection (DFI, 5.2%), and thromboembolism (4.5%). After COVID-19 pneumonia, MACE was the predominant cause of death in the first 2 weeks but declined thereafter. No death occurred due to bacteremia, HAP, or DFI in the first week after hospitalization, but became increasingly common with increased length of stay in the hospital accounting for 9%, 12%, and 10% of all deaths after 4 weeks in the hospital, respectively. CONCLUSION: Nearly one-third of patients with COVID-19 infection die of non-COVID-19 causes, some of which are preventable. Mitigation strategies should be instituted to reduce the risk of such deaths.

Long-term COVID-19 booster effectiveness by infection history and clinical vulnerability and immune imprinting: a retrospective population-based cohort study.

BACKGROUND: Long-term effectiveness of COVID-19 mRNA boosters in populations with different previous infection histories and clinical vulnerability profiles is inadequately understood. We aimed to investigate the effectiveness of a booster (third dose) vaccination against SARS-CoV-2 infection and against severe, critical, or fatal COVID-19, relative to that of primary-series (two-dose) vaccination over a follow-up duration of 1 year. METHODS: This observational, matched, retrospective, cohort study was done on the population of Qatar in people with different immune histories and different clinical vulnerability to infection. The source of data are Qatar's national databases for COVID-19 laboratory testing, vaccination, hospitalisation, and death. Associations were estimated using inverse-probability-weighted Cox proportional-hazards regression models. The primary outcome of the study is the effectiveness of COVID-19 mRNA boosters against infection and against severe COVID-19. FINDINGS: Data were obtained for 2 228 686 people who had received at least two vaccine doses starting from Jan 5, 2021, of whom 658 947 (29·6%) went on to receive a third dose before data cutoff on Oct 12, 2022. There were 20 528 incident infections in the three-dose cohort and 30 771 infections in the two-dose cohort. Booster effectiveness relative to primary series was 26·2% (95% CI 23·6-28·6) against infection and 75·1% (40·2-89·6) against severe, critical, or fatal COVID-19, during 1-year follow-up after the booster. Among people clinically vulnerable to severe COVID-19, effectiveness was 34·2% (27·0-40·6) against infection and 76·6% (34·5-91·7) against severe, critical, or fatal COVID-19. Effectiveness against infection was highest at 61·4% (60·2-62·6) in the first month after the booster but waned thereafter and was modest at only 15·5% (8·3-22·2) 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 albeit with wide CIs. Similar patterns of protection were observed irrespective of previous infection status, clinical vulnerability, or type of vaccine (BNT162b2 vs mRNA-1273). INTERPRETATION: Protection against omicron infection waned after the booster, and eventually suggested a possibility for negative immune imprinting. However, boosters substantially reduced infection and severe COVID-19, particularly among individuals who were clinically vulnerable, affirming the public health value of booster vaccination. FUNDING: The 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, and Qatar University Biomedical Research Center.

A new One Health Framework in Qatar for future emerging and re-emerging zoonotic diseases preparedness and response.

One Health is increasingly recognized as an optimal approach to address the global risk of health threats originating at the human, animal, and ecosystem interface, and their impact. Qatar has successfully practiced One Health approach for investigation and surveillance of zoonotic diseases such as MERS-CoV, and other health threats. However, the current gaps at institution and policy level hinder the sustainment of One Health. In this paper, we have assessed the potential for implementation of One Health Framework to reinforce and sustain One Health capacities in Qatar for 2022-2027. To implement One Health Framework in the country, Qatar Joint External Evaluation (JEE) report, lessons learnt during One Health experiences on zoonotic, vector-borne, and food borne diseases were used to present an outline for multisectoral coordination. In addition, technical capacities of One Health and factors that are required to operationalize it in the country were also assessed in series of meetings and workshops held at Ministry of Public Health on March 2022. Present health care infrastructure and resources were found to be conducive for effective management and response to shared health threats as evident during MERS-CoV, despite being more event based. Regardless, the need for more sustainable capacity development was unanimously emphasized. The consensus between all relevant stakeholders and partners was that there is a need for better communication channels, policies and protocols for data sharing, and the need to invest more resources for better sustainability. The proposed framework is expected to strengthen and facilitate multilateral coordination, enhanced laboratory capacity and network, improve active surveillance and response, risk communication, community engagement, maximize applied research, and build One Health technical work force. This would enable advancement and sustainment of One Health activities to prevent and control health threats shared between humans-animals-ecosystem interface.

Evaluation of mortality attributable to SARS-CoV-2 vaccine administration using national level data from Qatar.

Accurate determination of mortality attributable to SARS-CoV-2 vaccination is critical in allaying concerns about their safety. We reviewed every death in Qatar that occurred within 30 days of any SARS-CoV-2 vaccine administration between January 1, 2021 and June 12, 2022. Probability of association with SARS-CoV-2 vaccination was determined by four independent trained reviewers using a modified WHO algorithm. Among 6,928,359 doses administered, 138 deaths occurred within 30 days of vaccination; eight had a high probability (1.15/1,000,000 doses), 15 had intermediate probability (2.38/1,000,000 doses), and 112 had low probability or no association with vaccination. The death rate among those with high probability of relationship to SARS-CoV-2 vaccination was 0.34/100,000 unique vaccine recipients, while death rate among those with either high or intermediate probability of relationship to SARS-CoV-2 vaccination was 0.98/100,000 unique vaccine recipients. In conclusion, deaths attributable to SARS-CoV-2 vaccination are extremely rare and lower than the overall crude mortality rate in Qatar.

Effectiveness of influenza vaccination against SARS-CoV-2 infection among healthcare workers in Qatar.

BACKGROUND: Some studies have reported that influenza vaccination is associated with lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or coronavirus disease 2019 (COVID-19) morbidity and mortality. This study aims to estimate effectiveness of influenza vaccination, using Abbott's quadrivalent Influvac Tetra vaccine, against SARS-CoV-2 infection and against severe COVID-19. METHODS: This matched, test-negative, case-control study was implemented on a population of 30,774 healthcare workers (HCWs) in Qatar during the 2020 annual influenza vaccination campaign, September 17, 2020-December 31, 2020, before introduction of COVID-19 vaccination. RESULTS: Of 30,774 HCWs, 576 with PCR-positive tests and 10,033 with exclusively PCR-negative tests were eligible for inclusion in the study. Matching by sex, age, nationality, reason for PCR testing, and PCR test date yielded 518 cases matched to 2058 controls. Median duration between influenza vaccination and the PCR test was 43 days (IQR, 29-62). Estimated effectiveness of influenza vaccination against SARS-CoV-2 infection> 14 days after receiving the vaccine was 29.7% (95% CI: 5.5-47.7%). Estimated effectiveness of influenza vaccination against severe, critical, or fatal COVID-19 was 88.9% (95% CI: 4.1-98.7%). Sensitivity analyses confirmed the main analysis results. CONCLUSIONS: Recent influenza vaccination is associated with a significant reduction in the risk of SARS-CoV-2 infection and COVID-19 severity.

Detection of Antinuclear Antibodies Targeting Intracellular Signal Transduction, Metabolism, Apoptotic Processes and Cell Death in Critical COVID-19 Patients.

Background and Objectives: The heterogeneity of the coronavirus disease of 2019 (COVID-19) lies within its diverse symptoms and severity, ranging from mild to lethal. Acute respiratory distress syndrome (ARDS) is a leading cause of mortality in COVID-19 patients, characterized by a hyper cytokine storm. Autoimmunity is proposed to occur as a result of COVID-19, given the high similarity of the immune responses observed in COVID-19 and autoimmune diseases. Here, we investigate the level of autoimmune antibodies in COVID-19 patients with different severities. Results: Initial screening for antinuclear antibodies (ANA) IgG using ELISA revealed that 1.58% (2/126) and 4% (5/126) of intensive care unit (ICU) COVID-19 cases expressed strong and moderate ANA levels, respectively. An additional sample was positive with immunofluorescence assays (IFA) screening. However, all the non-ICU cases (n=273) were ANA negative using both assays. Samples positive for ANA were further confirmed with large-scale autoantibody screening by phage immunoprecipitation-sequencing (PhIP-Seq). The majority of the ANA-positive samples showed "speckled" ANA pattern by microscopy and revealed autoantibody specificities that targeted proteins involved in intracellular signal transduction, metabolism, apoptotic processes, and cell death by PhIP-Seq; further denoting reactivity to nuclear and cytoplasmic antigens. Conclusion: Our results further support the notion of routine screening for autoimmune responses in COVID-19 patients, which might help improve disease prognosis and patient management. Further, results provide compelling evidence that ANA-positive individuals should be excluded from being donors for convalescent plasma therapy in the context of COVID-19.

Protection from previous natural infection compared with mRNA vaccination against SARS-CoV-2 infection and severe COVID-19 in Qatar: a retrospective cohort study.

BACKGROUND: Understanding 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. METHODS: We 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. FINDINGS: Between 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. INTERPRETATION: Previous 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. FUNDING: 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.

Covid-19 Vaccine Protection among Children and Adolescents in Qatar.

BACKGROUND: The BNT162b2 vaccine against coronavirus disease 2019 (Covid-19) has been authorized for use in children 5 to 11 years of age and adolescents 12 to 17 years of age but in different antigen doses. METHODS: We assessed the real-world effectiveness of the BNT162b2 vaccine against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children and adolescents in Qatar. To compare the incidence of SARS-CoV-2 infection in the national cohort of vaccinated participants with the incidence in the national cohort of unvaccinated participants, we conducted three matched, retrospective, target-trial, cohort studies - one assessing data obtained from children 5 to 11 years of age after the B.1.1.529 (omicron) variant became prevalent and two assessing data from adolescents 12 to 17 years of age before the emergence of the omicron variant (pre-omicron study) and after the omicron variant became prevalent. Associations were estimated with the use of Cox proportional-hazards regression models. RESULTS: Among children, the overall effectiveness of the 10-µg primary vaccine series against infection with the omicron variant was 25.7% (95% confidence interval [CI], 10.0 to 38.6). Effectiveness was highest (49.6%; 95% CI, 28.5 to 64.5) right after receipt of the second dose but waned rapidly thereafter and was negligible after 3 months. Effectiveness was 46.3% (95% CI, 21.5 to 63.3) among children 5 to 7 years of age and 16.6% (95% CI, -4.2 to 33.2) among those 8 to 11 years of age. Among adolescents, the overall effectiveness of the 30-µg primary vaccine series against infection with the omicron variant was 30.6% (95% CI, 26.9 to 34.1), but many adolescents had been vaccinated months earlier. Effectiveness waned over time since receipt of the second dose. Effectiveness was 35.6% (95% CI, 31.2 to 39.6) among adolescents 12 to 14 years of age and 20.9% (95% CI, 13.8 to 27.4) among those 15 to 17 years of age. In the pre-omicron study, the overall effectiveness of the 30-µg primary vaccine series against SARS-CoV-2 infection among adolescents was 87.6% (95% CI, 84.0 to 90.4) and waned relatively slowly after receipt of the second dose. CONCLUSIONS: Vaccination in children was associated with modest, rapidly waning protection against omicron infection. Vaccination in adolescents was associated with stronger, more durable protection, perhaps because of the larger antigen dose. (Funded by Weill Cornell Medicine-Qatar and others.).

Duration of immune protection of SARS-CoV-2 natural infection against reinfection.

BACKGROUND: The 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. METHODS: Three 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. RESULTS: Effectiveness 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 < 10% by the 32nd 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 < 10% by the 15th 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. 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.

Effects of SARS-CoV-2 Alpha, Beta, and Delta variants, age, vaccination, and prior infection on infectiousness of SARS-CoV-2 infections

In 2021, Qatar experienced considerable incidence of SARS-CoV-2 infection that was dominated sequentially by the Alpha, Beta, and Delta variants. Using the cycle threshold (Ct) value of an RT-qPCR-positive test to proxy the inverse of infectiousness, we investigated infectiousness of SARS-CoV-2 infections by variant, age, sex, vaccination status, prior infection status, and reason for testing in a random sample of 18,355 RT-qPCR-genotyped infections. Regression analyses were conducted to estimate associations with the Ct value of RT-qPCR-positive tests. Compared to Beta infections, Alpha and Delta infections demonstrated 2.56 higher Ct cycles (95% CI: 2.35-2.78), and 4.92 fewer cycles (95% CI: 4.67- 5.16), respectively. The Ct value declined gradually with age and was especially high for children <10 years of age, signifying lower infectiousness in small children. Children <10 years of age had 2.18 higher Ct cycles (95% CI: 1.88-2.48) than those 10-19 years of age. Compared to unvaccinated individuals, the Ct value was higher among individuals who had received one or two vaccine doses, but the Ct value decreased gradually with time since the second-dose vaccination. Ct value was 2.07 cycles higher (95% CI: 1.42-2.72) for those with a prior infection than those without prior infection. The Ct value was lowest among individuals tested because of symptoms and was highest among individuals tested as a travel requirement. Delta was substantially more infectious than Beta. Prior immunity, whether due to vaccination or prior infection, is associated with lower infectiousness of breakthrough infections, but infectiousness increases gradually with time since the second-dose vaccination.

Effectiveness of the neutralizing antibody sotrovimab among high-risk patients with mild-to-moderate SARS-CoV-2 in Qatar.

OBJECTIVES: To estimate the real-world effectiveness of sotrovimab against severe, critical, or fatal COVID-19 in Qatar at a time in which most SARS-CoV-2 incidences occurred due to the BA.2 Omicron subvariant. METHODS: We conducted a matched case-control study among all individuals eligible for sotrovimab treatment per United States Food and Drug Administration guidelines in the resident population of Qatar. The odds of progression to severe forms of COVID-19 were compared in cases (treatment group) versus controls (eligible patients who opted not to receive the treatment). Subgroup analyses were conducted. RESULTS: A total of 3364 individuals were eligible for sotrovimab treatment during the study period, of whom 519 individuals received the treatment, whereas the remaining 2845 constituted the controls. The adjusted odds ratio of disease progression to severe, critical, or fatal COVID-19 comparing the treatment group to the control group was 2.67 (95% confidence interval 0.60-11.91). In the analysis including only the subgroup of patients at higher risk of severe forms of COVID-19, the adjusted odds ratio was 0.65 (95% confidence interval 0.17-2.48). CONCLUSION: There was no evidence for a protective effect of sotrovimab in reducing COVID-19 severity in a setting dominated by the BA.2 subvariant.

Severity, Criticality, and Fatality of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Beta Variant.

Beta (B.1.351)-variant coronavirus disease 2019 (COVID-19) disease was investigated in Qatar. Compared with the Alpha (B.1.1.7) variant, odds (95% confidence interval) of progressing to severe disease, critical disease, and COVID-19-related death were 1.24-fold (1.11-1.39), 1.49-fold (1.13-1.97), and 1.57-fold (1.03-2.43) higher, respectively, for the Beta variant.

COVID-19 Disease Severity in Persons Infected With Omicron BA.1 and BA.2 Sublineages and Association With Vaccination Status.

This retrospective study compares the severity of SARS-CoV-2 infection among persons infected with BA.1 and BA.2 sublineages by vaccination status.