for the National COVID Cohort Collaborative (N3C) Consortium IMPORTANCE Persons with immune dysfunction have a higher risk for severe COVID-19 outcomes. However, these patients were largely excluded from SARS-CoV-2 vaccine clinical trials, creating a large evidence gap.OBJECTIVE To identify the incidence rate and incidence rate ratio (IRR) for COVID-19 breakthrough infection after SARS-CoV-2 vaccination among persons with or without immune dysfunction. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study analyzed data from the National COVID Cohort Collaborative (N3C), a partnership that developed a secure, centralized electronic medical record-based repository of COVID-19 clinical data from academic medical centers across the US. Persons who received at least 1 dose of a SARS-CoV-2 vaccine between December 10, 2020, and September 16, 2021, were included in the sample.MAIN OUTCOMES AND MEASURES Vaccination, COVID-19 diagnosis, immune dysfunction diagnoses (ie, HIV infection, multiple sclerosis, rheumatoid arthritis, solid organ transplant, and bone marrow transplantation), other comorbid conditions, and demographic data were accessed through the N3C Data Enclave. Breakthrough infection was defined as a COVID-19 infection that was contracted on or after the 14th day of vaccination, and the risk after full or partial vaccination was assessed for patients with or without immune dysfunction using Poisson regression with robust SEs. Poisson regression models were controlled for a study period (before or after [pre-or post-Delta variant] June 20, 2021), full vaccination status, COVID-19 infection before vaccination, demographic characteristics, geographic location, and comorbidity burden.RESULTS A total of 664 722 patients in the N3C sample were included. These patients had a median (IQR) age of 51 (34-66) years and were predominantly women (n = 378 307 [56.9%]). Overall, the incidence rate for COVID-19 breakthrough infection was 5.0 per 1000 person-months among fully vaccinated persons but was higher after the Delta variant became the dominant SARS-CoV-2 strain (incidence rate before vs after June 20, 2021, 2.2 [95% CI, 2.2-2.2] vs 7.3 [95% CI,] per 1000 person-months). Compared with partial vaccination, full vaccination was associated with a 28% reduced risk for breakthrough infection (adjusted IRR [AIRR], 0.72; 95% CI, 0.68-0.76). People with a breakthrough infection after full vaccination were more likely to be older and women. People with HIV infection (AIRR, 1.33; 95% CI, 1.18-1.49), rheumatoid arthritis (AIRR, 1.20; 95% CI, 1.09-1.32), and solid organ transplant (AIRR, 2.16; 95% CI, 1.96-2.38) had a higher rate of breakthrough infection.CONCLUSIONS AND RELEVANCE This cohort study found that full vaccination was associated with reduced risk of COVID-19 breakthrough infection, regardless of the immune status of patients. Despite full vaccination, persons with immune dysfunction had substantially higher risk for COVID-19 breakthrough infection than those without such a condition. For persons with immune...

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PURPOSE Variation in risk of adverse clinical outcomes in patients with cancer and COVID-19 has been reported from relatively small cohorts. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multicenter cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cancer cohort within N3C and identify risk factors for all-cause mortality from COVID-19. METHODS We used 4,382,085 patients from 50 US medical centers to construct a cohort of patients with cancer. We restricted analyses to adults ≥ 18 years old with a COVID-19–positive or COVID-19–negative diagnosis between January 1, 2020, and March 25, 2021. We followed N3C selection of an index encounter per patient for analyses. All analyses were performed in the N3C Data Enclave Palantir platform. RESULTS A total of 398,579 adult patients with cancer were identified from the N3C cohort; 63,413 (15.9%) were COVID-19–positive. Most common represented cancers were skin (13.8%), breast (13.7%), prostate (10.6%), hematologic (10.5%), and GI cancers (10%). COVID-19 positivity was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.20; 95% CI, 1.15 to 1.24). Among COVID-19–positive patients, age ≥ 65 years, male gender, Southern or Western US residence, an adjusted Charlson Comorbidity Index score ≥ 4, hematologic malignancy, multitumor sites, and recent cytotoxic therapy were associated with increased risk of all-cause mortality. Patients who received recent immunotherapies or targeted therapies did not have higher risk of overall mortality. CONCLUSION Using N3C, we assembled the largest nationally representative cohort of patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in patients with cancer. Full characterization of the cohort will provide further insights into the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments.

PURPOSE To provide real-world evidence on risks and outcomes of breakthrough COVID-19 infections in vaccinated patients with cancer using the largest national cohort of COVID-19 cases and controls. METHODS We used the National COVID Cohort Collaborative (N3C) to identify breakthrough infections between December 1, 2020, and May 31, 2021. We included patients partially or fully vaccinated with mRNA COVID-19 vaccines with no prior SARS-CoV-2 infection record. Risks for breakthrough infection and severe outcomes were analyzed using logistic regression. RESULTS A total of 6,860 breakthrough cases were identified within the N3C-vaccinated population, among whom 1,460 (21.3%) were patients with cancer. Solid tumors and hematologic malignancies had significantly higher risks for breakthrough infection (odds ratios [ORs] = 1.12, 95% CI, 1.01 to 1.23 and 4.64, 95% CI, 3.98 to 5.38) and severe outcomes (ORs = 1.33, 95% CI, 1.09 to 1.62 and 1.45, 95% CI, 1.08 to 1.95) compared with noncancer patients, adjusting for age, sex, race/ethnicity, smoking status, vaccine type, and vaccination date. Compared with solid tumors, hematologic malignancies were at increased risk for breakthrough infections (adjusted OR ranged from 2.07 for lymphoma to 7.25 for lymphoid leukemia). Breakthrough risk was reduced after the second vaccine dose for all cancers (OR = 0.04; 95% CI, 0.04 to 0.05), and for Moderna's mRNA-1273 compared with Pfizer's BNT162b2 vaccine (OR = 0.66; 95% CI, 0.62 to 0.70), particularly in patients with multiple myeloma (OR = 0.35; 95% CI, 0.15 to 0.72). Medications with major immunosuppressive effects and bone marrow transplantation were strongly associated with breakthrough risk among the vaccinated population. CONCLUSION Real-world evidence shows that patients with cancer, especially hematologic malignancies, are at higher risk for developing breakthrough infections and severe outcomes. Patients with vaccination were at markedly decreased risk for breakthrough infections. Further work is needed to assess boosters and new SARS-CoV-2 variants.

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