Molnupiravir Use and 30-Day Hospitalizations or Death in Previously Uninfected Non-hospitalized High-risk Population with COVID-19.

BACKGROUND: Clinical benefit of Molnupiravir (MPV) in COVID-19 infected sub-populations is unclear. METHODS: We used a matched cohort study design to determine the rate of hospitalization or death within 30 days of COVID-19 diagnosis among MPV treated and untreated controls. Participants were non-hospitalized, previously uninfected Veterans with a first confirmed SARS-CoV-2 infection between January 1 and August 31, 2022, who were prescribed MPV within 3 days of COVID-19 diagnosis, and matched individuals who were not prescribed MPV. RESULTS: Among 1,459 matched pairs, the incidence of hospitalization/death was not different among MPV treated vs. untreated controls (48 vs. 44 cases; ARD [95% CI] 0.27 [-0.94,1.49]). No benefit was observed among those >60 or ≤60 years old (ARD 0.27 [-1.25,1.79] vs. -0.29 [-1.22,1.80]), those with specific comorbidities, or by vaccination status. A significant benefit was observed in asymptomatic but not in symptomatic persons (ARD -2.80 [-4.74, -0.87] vs. 1.12 [-0.31,2.55]). Kaplan-Meier curves did not show a difference in proportion of persons who were hospitalized or died among MPV treated compared with untreated controls (logrank P = 0.7). CONCLUSION: MPV was not associated with a reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms experienced a benefit.

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.

Comparative COVID-19 Vaccine Effectiveness Over Time in Veterans.

Background: Comparative effectiveness of coronavirus disease 2019 (COVID-19) vaccines across patient subgroups is poorly understood and essential to precisely targeting vaccination strategies. Methods: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infection before December 11, 2020. Using a test-negative case-control design (TND), we used conditional logistic regression with adjustment for covariates to estimate vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Results: We identified 4.8 million veterans with a mean age of 64 years, of whom 58% had ≥1 chronic disease. Vaccine effectiveness for symptomatic infections, hospitalizations, and ICU admission or death declined over time and varied by the type of vaccine (P < 0.01). VE estimates against symptomatic infection during months 1 and 7 for mRNA-1273 compared with BNT162b2 were 89.7% (95% CI, 84.4%-93.0%) and 57.3% (95% CI, 48.4%-64.7%) vs 81.6% (95% CI, 75.9%-85.9%) and 22.5% (95% CI, 7.2%-35.2%) for individuals age <65 years and 78.4% (95% CI, 71.1%-83.9%) and 36.2% (95% CI, 27.7%-43.6%) vs 66.3% (95% CI, 55.7%-74.4%) and -23.3% (95% CI, -40.5% to -8.2%) in subjects age ≥65 years; against hospitalization 92.0% (95% CI, 76.1%-97.3%) and 83.1% (95% CI, 66.8%-91.4%) vs 85.6% (95% CI, 72.6%-92.4%) and 57.0% (95% CI, 31.2%-73.2%) in subjects age <65 years and 66.1% (95% CI, 45.3%-79.0%) and 64.7% (95% CI, 55.2%-72.3%) vs 61.0% (95% CI, 41.3%-74.2%) and 1.7% (95% CI, -22.0% to 20.8%) in those age ≥65 years; against ICU admission or death 89.2% (95% CI, 49.5%-97.7%) and 84.4% (95% CI, 59.0%-94.1%) vs 87.6% (95% CI, 61.0%-96.1%) and 66.4% (95% CI, 7.7%-87.8%) in subjects age <65 years and 75.4% (95% CI, 51.7%-87.5%) and 73.8 (95% CI, 62.9%-81.5%) vs 67.4% (95% CI, 32.6%-84.3%) and 29.3% (95% CI, 2.3%-48.9%) in subjects age ≥65 years, respectively (P interaction < .01 for all comparisons). Similarly, mRNA-1273 was more effective than BNT162b2 in veterans with >1 chronic disease. Conclusions: mRNA-1273 was more effective than BNT162b2 in older veterans and those with chronic diseases.

Effectiveness of Messenger RNA Vaccines against SARS-CoV-2 Infection in Hemodialysis Patients: A Case-Control Study.

Patients with end-stage kidney disease (ESKD) are at increased risk for SARS-CoV-2 infection and its complications compared with the general population. Several studies evaluated the effectiveness of COVID-19 vaccines in the dialysis population but showed mixed results. The aim of this study was to determine the effectiveness of COVID-19 mRNA vaccines against confirmed SARS-CoV-2 infection in hemodialysis (HD) patients in the State of Qatar. We included all adult ESKD patients on chronic HD who had at least one SARS-CoV-2 PCR test done after the introduction of the COVID-19 mRNA vaccines on 24 December 2020. Vaccinated patients who were only tested before receiving any dose of their COVID-19 vaccine or within 14 days after receiving the first vaccine dose were excluded from the study. We used a test-negative case−control design to determine the effectiveness of the COVID-19 vaccination. Sixty-eight patients had positive SARS-CoV-2 PCR tests (cases), while 714 patients had negative tests (controls). Ninety-one percent of patients received the COVID-19 mRNA vaccine. Compared with the controls, the cases were more likely to be older (62 ± 14 vs. 57 ± 15, p = 0.02), on dialysis for more than one year (84% vs. 72%, p = 0.03), unvaccinated (46% vs. 5%, p < 0.0001), and symptomatic (54% vs. 21%, p < 0.0001). The effectiveness of receiving two doses of COVID-19 mRNA vaccines against confirmed SARS-CoV-2 infection was 94.7% (95% CI: 89.9−97.2) in our HD population. The findings of this study support the importance of using the COVID-19 mRNA vaccine in chronic HD patients to prevent SARS-CoV-2 infection in such a high-risk population.

Relative Vaccine Effectiveness of a SARS-CoV-2 mRNA Vaccine Booster Dose Against the Omicron Variant.

BACKGROUND: The current SARS-CoV-2 vaccines may be less effective against the Omicron variant. With recent resurgence of SARS-CoV-2 cases, the role of booster doses of the vaccine needs to be highlighted. METHODS: Using a retrospective cohort study design emulating a target trial, we determined the relative effectiveness of a homologous booster dose of a SARS-CoV-2 mRNA vaccine compared with primary series alone in preventing infection, hospitalization, and intensive care unit (ICU) admission, and death in the Department of Veterans Affairs healthcare system in the US. Among infection-free survivors who received two doses of an mRNA vaccine prior to April 30, 2021, we identified those who received a booster between September 22 and December 25, 2021 and 1:1 matched individuals who did not receive a booster. RESULTS: Among 2,384,272 previously uninfected persons with two doses of an mRNA vaccine by April 30, 2021, we identified 462,950 booster recipients between September 22 and December 25, 2021 who were matched 1:1 with non-booster recipients. RVE (95% CI) was 19% (17-22%) for confirmed infection, 52% (46-57%) for hospitalization, and 83% (65-92%) for ICU admission or death. Recipients of the mRNA-1273 vaccine had a lower cumulative incidence of infections and hospitalizations compared with BNT-162b2 vaccine (log-rank p-value <0.001 for both comparisons). CONCLUSION: While the RVE of SARS-CoV-2 mRNA booster vaccine dose in preventing infection against the Omicron variant is low, the RVE is substantial in preventing hospitalization and high in preventing the most severe/critical disease.

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.

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.).

Variation in Clinical Treatment and Outcomes by Race Among US Veterans Hospitalized With COVID-19.

Importance: Patients from racially and ethnically minoritized populations, such as Black and Hispanic patients, may be less likely to receive evidence-based COVID-19 treatments than White patients, contributing to adverse clinical outcomes. Objective: To determine whether clinical treatments and outcomes among patients hospitalized with COVID-19 were associated with race. Design, Setting, and Participants: This retrospective cohort study was conducted in 130 Department of Veterans Affairs Medical Centers (VAMCs) between March 1, 2020, and February 28, 2022, with a 60-day follow-up period until May 1, 2022. Participants included veterans hospitalized with COVID-19. Data were analyzed from May 6 to June 2, 2022. Exposures: Self-reported race. Main Outcomes and Measures: Clinical care processes (eg, intensive care unit [ICU] admission; organ support measures, including invasive and noninvasive mechanical ventilation; prone position therapy, and COVID-19-specific medical treatments) were quantified. Clinical outcomes of interest included in-hospital mortality, 60-day mortality, and 30-day readmissions. Outcomes were assessed with multivariable random effects logistic regression models to estimate the association of race with outcomes not attributable to known mediators, such as socioeconomic status and age, while adjusting for potential confounding between outcomes and mediators. Results: A total of 43 222 veterans (12 135 Black veterans [28.1%]; 31 087 White veterans [71.9%]; 40 717 [94.2%] men) with a median (IQR) age of 71 (62-77) years who were hospitalized with SARS-CoV-2 infection were included. Controlling for site of treatment, Black patients were equally likely to be admitted to the ICU (4806 Black patients [39.6%] vs 13 427 White patients [43.2%]; within-center adjusted odds ratio [aOR], 0.95; 95% CI, 0.88-1.02; P = .17). Two-thirds of patients treated with supplemental oxygen or noninvasive or invasive mechanical ventilation also received systemic steroids, but Black veterans were less likely to receive steroids (within-center aOR, 0.88; 95% CI, 0.80-0.96; P = .004; between-center aOR, 0.67; 95% CI, 0.48-0.96; P = .03). Similarly, Black patients were less likely to receive remdesivir (within-center aOR, 0.89; 95% CI, 0.83-0.95; P < .001; between-center aOR, 0.68; 95% CI, 0.47-0.99; P = .02) or treatment with immunomodulatory drugs (within-center aOR, 0.77; 95% CI, 0.67-0.87; P < .001). After adjusting for patient demographic characteristics, chronic health conditions, severity of acute illness, and receipt of COVID-19-specific treatments, there was no association of Black race with hospital mortality (within-center aOR, 0.98; 95% CI, 0.86-1.10; P = .71) or 30-day readmission (within-center aOR, 0.95; 95% CI, 0.88-1.04; P = .28). Conclusions and Relevance: These findings suggest that Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based COVID-19 treatments, including systemic steroids, remdesivir, and immunomodulatory drugs.

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.