Covid-19 Bivalent Booster Effectiveness in People with and without Immune Dysfunction

Background: Data on the effectiveness of the bivalent booster vaccine against COVID-19 breakthrough infection and severe outcomes is limited. Method(s): Using patient-level data from 54 sites in the U.S. National COVID Cohort Collaborative (N3C), we estimated bivalent booster effectiveness against breakthrough infection and outcomes between 09/01/2022 (bivalent vaccine approval date) to 12/15/2022 (most recent data release of N3C) among patients completed 2+ doses of mRNA vaccine. Bivalent booster effectiveness was evaluated among all patients and patients with and without immunosuppressed/compromised conditions (ISC;HIV infection, solid organ/ bone marrow transplant, autoimmune diseases, and cancer). We used logistic regression models to compare the odds of breakthrough infection (COVID-19 diagnosis after the last dose of vaccine) and outcomes (hospitalization, ventilation/ECMO use, or death <=28 days after infection) in the bivalent boosted vs. non-bivalent boosted groups. Models controlled for demographics, comorbidities, geographic region, prior SARS-CoV-2 infection, months since the last dose of non-bivalent vaccine, and prior non-bivalent booster. Result(s): By 12/15/2022, 2,414,904 patients had received 2+ doses of mRNA vaccination, 75,873 of them had received a bivalent booster vaccine, and 24,046 of them had a breakthrough infection. At baseline, the median age was 52 (IQR 36-67) years, 40% male, 63% white, 10% Black, 12% Latinx, 3.5% Asian American/Pacific Islander, and 14% were patients with ISC. Patients received a bivalent booster were more likely to be female and had comorbidities. Bivalent booster was significantly associated with reduced odds of breakthrough infection and hospitalization (Figure). The adjusted odds ratios comparing bivalent vs. non-bivalent group were 0.28 (95% CI 0.25, 0.32) for all patients and 0.33 (95% CI: 0.26, 0.41) for patients with ISC. Compared to the nonbivalent group, the bivalent group had a lower incidence of COVID-19-related hospitalization (151 vs. 41 per 100,000 persons), invasive ventilation/ECMO use (7.5 vs. 1.3 per 100,000 persons), or death (11 vs. 1.3 per 100,000 persons) in all patients during the study period;the incidence of severe outcomes after bivalent boosting was similar among patients with and without ISC. Conclusion(s): A bivalent booster vaccine was highly effective against COVID-19 breakthrough infection and severe outcomes among patients received 2+ doses of mRNA vaccine and offered similar protection in patients with and without ISC. (Figure Presented).

Hormone Replacement Therapy and COVID-19 Outcomes in Kidney Transplant Recipients Compared With the General Population

Background: In the non-immunosuppressed (non-IS) population, female sex is protective against adverse COVID-19 (C19) outcomes, possibly due to estrogenrelated immunity. Sex-based risk is attenuated in IS kidney transplant recipients (KTRs). Exogenous estrogen is associated with reduced C19 mortality in non-IS postmenopausal females. Here, we aimed to study the impact of estrogen or testosterone hormone replacement therapy (HRT) on C19 outcomes in KTRs compared to the general population. Method(s): We studied adult (>45 yrs) KTRs from across the US with C19 from 05-01-20 to 05-12-22, using EHR data from the National COVID Cohort Collaborative. Female and male patients were classified as no HRT, or HRT use in the last 6 months (exogenous systemic estrogens for females;testosterone for males). Using MV cox proportional hazards models and logistic regression, we determined the risk of developing a major adverse renal or cardiac event (MARCE), mortality, and other 90-day post-C19 outcomes. We repeated this analysis in a non-IS control group for comparison. Result(s): Over the study period, 11,498 KTRs and >1.9M non-IS patients were diagnosed with C19. In non-IS, relative to no HRT use, HRT use in the last 6 months was associated with significantly lower risk of MARCE (Hazard Ratio [HR] 0.54, 95% Confidence Interval [CI] 0.51-0.59, for females;0.63, 0.56-0.70, for males), mortality (HR 0.45, CI 0.40-0.51, for females;0.55, 0.45-0.66, for males), and all secondary events for males and females (Figure 1). In KTRs, HRT was not associated with any post-C19 outcome in either males or females;there was a trend towards lower risk in males on HRT vs not on HRT, for most outcomes. Conclusion(s): HRT was protective against adverse C19 outcomes in older non-IS males and females, but not in KTRs. The modifying effects of IS on the benefits of HRT requires further investigation.

Role of Vaccination in the COVID-19 Nationwide Cohort (N3C) of Solid Organ Transplant Recipients

Purpose: Immunosuppressed solid organ transplant (SOT) patients have been repeatedly challenged in the COVID-19 pandemic with significant morbidities and mortality following infection and a suppressed immune response to vaccination. The aim of this study was to assess the impact on COVID-19 morbidity and mortality in the presence and absence of vaccination. Method(s): We studied adult (>18 years) patients from across the United States identified using the National COVID Cohort Collaborative (N3C) Enclave from Dec 10, 2020-Oct 12, 2021. Using multivariable logistic regression, we determined the odds of developing COVID-19 infection in the 6 months after full vaccination (defined as a breakthrough (BT) infection) in SOT recipients relative to nonimmunosuppressed (non-IS) patients. In SOT patients with BT COVID-19 infection, we then used multivariable logistic regression to determine the association of full and partial vaccination status with major adverse cardiac events, mortality, and additional secondary outcomes in the 90 days following COVID-19 diagnosis relative to unvaccinated/unconfirmed vaccination status SOT recipients). Result(s): Over the study period, 16,075 SOT patients were diagnosed with COVID-19 (515 were partially vaccinated, and 1,868 were fully vaccinated). Relative to non- IS, SOT was associated with an increased odds of BT COVID-19 infection in the 6 months post vaccine, that varied by organ type (i.e. OR 1.97, 95% CI 1.75-2.25 for kidney;OR 2.30, 95% CI 1.70-3.06 for lung), Table 1. In SOT patients who experienced BT COVID-19, full vaccination was associated with a small reduction in adverse outcomes relative to unvaccinated/unconfirmed vaccination status (OR 0.91, 95% CI 0.89-0.93 for MARCE;OR 0.92, 95% CI 0.90-0.93 for death;OR 0.90, 95% CI 0.88-0.92 for hospitalization), Table 2. Conclusion(s): SOT patients are at a ~2-fold increased odds of BT COVID-19 infection after vaccination compared with non-IS patients. Vaccination in SOT patients, regardless of product, has a small but significant reduction in the risk of adverse outcomes after a diagnosis of COVID-19, however SOT recipients remain at high risk and should continue to use caution even after vaccination. (Table Presented).

COVID-19 BOOSTER VACCINE EFFECTIVENESS in PEOPLE with and WITHOUT IMMUNE DYSFUNCTION

Background: Real-world evidence on effectiveness of booster or additional doses of COVID-19 vaccine is limited. Methods: Using patient-level data from 50 sites in the U.S. National COVID Cohort Collaborative (N3C), we estimated COVID-19 booster vaccine effectiveness compared to full vaccination alone (completed 2 doses mRNA or 1 dose Janssen vaccine). At each month following full vaccination, we created comparable cohorts of patients with boosters propensity-score matched to those without boosters by age, sex, race/ethnicity, comorbidities, geographic region, prior COVID-19 infection, and calendar month of full vaccination. Booster efficacy was evaluated among patients with and without immunosuppressed/compromised conditions (ISC;HIV infection, solid organ or bone marrow transplant, autoimmune diseases, and cancer). We used Cox regression models to estimate hazards of breakthrough infection (COVID-19 diagnosis after last dose of vaccine) and logistic regression models to compare the risk of death ≤45 days after a breakthrough infection in the boosted vs. matched non-boosted groups. Results: By 11/18/2021, 656390 patients had received full vaccination, and 125409 fully vaccinated had received an additional booster (median time from last vaccine to booster dose: 7.4 months, IQR:6.6, 8.2). At completion of full vaccination, median age was 50 (IQR 33-64) years, 43% male, 50% white, 11% Black, 18% Latinx, 4.8% Asian American/Pacific Islander, and 20% had ISC. People receiving a booster were more likely to be older, male, white, and have ISC. Booster vaccine was significantly associated with a reduced hazard of breakthrough infection (Table). Booster efficacy ranged from 46% (booster receipt 1-4 months after full vaccination) to 83% (receipt 7 months after full vaccination) in people without ISC. Vaccine efficacy was lower, ranging from 43%-65%, in ISC patients (Table). Compared to fully vaccinated patients without booster receipt, patients with booster had an 83% (OR: 0.17, 95% CI: 0.11, 0.28) reduced risk of COVID-19 related death, independent of demographics, geographic region, comorbidities, ISC, prior COVID-19 infection, and time of full vaccination. Conclusion: A booster dose of COVID-19 vaccine has high effectiveness in reducing breakthrough infection risk among all fully vaccinated individuals, though only with moderate effectiveness among ISC patients. Nonetheless, booster vaccination significantly reduced risk for COVID-19 related death regardless of ISC status.

COVID-19 in solid organ transplantation (SOT): Results of the national covid cohort collaborative (N3C)

Purpose: SARS-CoV-2 infection has resulted in significant mortality in solid organ transplant (SOT) recipients based on reports from single centers or voluntary registries. The N3C Enclave was developed to facilitate analysis of patient-level data across the US for multiple conditions, consisting of weekly electronic medical record (EMR) data extraction and transmission into a federally secured platform. Herein is our report of the largest cohort of US COVID-19 positive SOT patients to date. Methods: We identified a cohort of SOT recipients who received a positive or negative COVID-19 test (COVID+ and COVID-, respectively) between 01/01/2020 and 11/23/2020. In COVID+ SOT, we evaluated outcomes including requirement for hospitalization, major adverse cardiac events (MACE), and graft rejection and failure occurring until study end. Significant differences between COVID+ and COVID- patients were identified using t-test and chi-square testing, as indicated. Results: 34 sites account for 2.15 million patients in the Enclave, of whom 292,226 are COVID+. We identified 19,031 SOT patients, of whom 2,183 were COVID+ (11.5%) with a median follow-up time of 119 days. Demographics are shown in Figure 1. Compared to COVID- SOT patients, COVID+ SOT patients were more likely to have a kidney transplant and be non-white or Hispanic. Hypertension, diabetes, coronary artery disease and chronic kidney disease were common comorbidities in all SOT, but significantly more common in those who were COVID+. Of COVID+ SOT, 51.8% required hospital admission for a median of 1 days (range 0-114). Following COVID diagnosis, 13.7% of COVID+ SOT patients experienced MACE, 3.8% had graft rejection and 3.4% had graft loss over the study period. Conclusions: In the largest US cohort of COVID+ SOT recipients to date, we identify patient factors associated with the diagnosis of COVID-19 and outcomes following infection including a relatively high incidence of MACE. This is an evolving dataset and provides novel opportunities for analyses of COVID in SOT recipients on a granular level.

COVID-19 hospitalization among people with HIV or solid organ transplant in the us

Background: The role of immunosuppression/compromise (ISC) in risk of severe COVID-19 is unknown. While ISC could reduce control of SARS-CoV-2 viremia, it might also dampen the severe immune response to the virus;data comparing ISC groups is limited. Methods: Using patient-level data from 34 sites in the U.S. National COVID Cohort Collaborative (N3C), we compared risk of COVID-19 hospitalization amongst COVID-19 patients in 3 ISC groups (1,300 persons with HIV [PWH];2,142 solid organ transplant [SOT] patients;41 PWH with SOT) to 288,743 COVID-19 patients without HIV or SOT (HIV-/SOT-). COVID-19+ was defined by RT-PCR, antibody test, or diagnostic codes. HIV infection, SOT and comorbidities were defined by conditions/diagnostic codes within 2 years prior to first COVID-19+. Hospitalization was defined by inpatient care between 14 days prior to 45 days after the first COVID-19+. Odds ratios of hospitalization were estimated using multivariable logistic regression models adjusting for demographics, study site, and comorbidities (severe liver disease, diabetes, cancer, kidney disease, and total comorbidities [0, 1, 2, ≥3]). Results: Of 292,226 COVID-19+ patients, the median age was 41 years (IQR: 25-58), 46% male, 47% non-Hispanic white (NHW), and 17% non-Hispanic black (NHB). PWH and SOT patients, respectively, were more likely to be older (median: 50 & 56), male (70% & 60%), and had ≥ 3 comorbidities than overall N3C patients (30% & 64% vs. 8%). PWH were more likely to be NHB (50%) and SOT patients were more likely to be NHW (41%). Overall, 26% of HIV-/ SOT- COVID-19 patients were hospitalized. In crude analyses with HIV-/SOT- as the referent group (Table), COVID-19 patients with HIV, SOT or both had a 2.3, 4.4, or 6.9-fold increased odds of hospitalization, respectively. After adjustment for demographics and site, the risk was attenuated but remained statistically significant (Model a). Sequential adjustment for the type and number of comorbidities obviated the estimated risk among PWH, while SOT patients had persistently increased odds of hospitalization (Model b). Conclusion: ISC patients (PWH and SOT) are more likely to be hospitalized with COVID-19 independent of demographics. However, this increased hospitalization risk was driven mainly by the high burden of comorbidities in both groups. Only SOT patients had an independent risk of hospitalization after adjusting for comorbidities. Ongoing analyses will examine the impact of ISC on additional COVID-19 outcomes (i.e. ventilation use, death).

Racial disparities in COVID-19 positivity among people living with HIV in the us

Background: Morbidity and mortality due to COVID-19 disproportionately impacts racial/ethnic minorities and adults with chronic diseases, potentially including people living with HIV (PLWH). Here, we present descriptive patient characteristics by COVID-19 positive and HIV status using the U.S. National COVID Cohort Collaborative (N3C). Methods: Using N3C data, we conducted a retrospective cohort analysis of patients aged ≥ 18 years that had undergone COVID-19 testing. The N3C cohort includes patients with any encounter after 1/1/2020 with SARS-CoV-2 laboratory tests or diagnostic codes. Detailed electronic medical records are centrally gathered and data harmonized across health care organizations (34 sites). COVID-19 positivity was defined by a positive RT-PCR or antibody testing . HIV infection was defined based on standard diagnostic codes within 2 years prior to COVID-19 testing. Patient characteristics by COVID-19 positive and HIV status were compared using 2 tests. Results: Over 2.1 million patients were captured in the N3C as of 11/25/2020, of whom 292,226 (13.6%) were COVID-19 positive;11,011 (0.5%) were PLWH of whom 1341 (12.2%) tested COVID-19 positive . Compared to HIV-negative patients with COVID-19, COVID-19-positive PLWH were more likely to be 45+ years of age (62.3% vs.43.8%, p<0.001), male (70% vs. 46%, p<0.001), treated on an outpatient basis (9% vs. 5%, p<0.001), and have a modified Charlson comorbidity index score ≥3 (80% vs. 10%,p<0.001). Non-Hispanic (NH) Black COVID-19 positive adults were more likely to have HIV (51% vs. 17%, p<0.001), whereas NH-White were less likely (24% vs. 47%, p<0.001) (Figure 1). When comparing to PLWH without COVID-19, PLWH with COVID-19 were less likely to have a modified Charlson comorbidity index score of 3 or above (27% vs. 32%, p<0.001), with no significant differences in age or sex. COVID-19 positive PLWH were more likely to be NH-Black (51% vs. 45%, p<0.001) and Hispanic (8% vs. 5%, p<0.001), and, conversely, less likely to be NH-White (24% vs. 36%, p<0.001 ) when compared to PLWH without COVID-19 (Figure 1). Conclusion: Racial/ethnic minorities, including NH-Black and Hispanic adults, are disproportionately affected by COVID-19 pandemic, including PLWH. Our ongoing analyses will shed light on underlying mechanisms, such as types of comorbidities, that may lead to racial/ethnic disparities in the concurrence of HIV and COVID-19 positivity in the US.