The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Trends in mortality in people with HIV from 1999 to 2020: a multi-cohort collaboration.

BACKGROUND: Mortality among people with HIV declined with the introduction of combination antiretroviral therapy. We investigated trends over time in all-cause and cause-specific mortality in people with HIV from 1999-2020. METHODS: Data were collected from the D:A:D cohort from 1999 through January 2015 and RESPOND from October 2017 through 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV (CoDe), were calculated. Poisson regression models were used to assess mortality trends over time. RESULTS: Among 55716 participants followed for a median of 6 years (IQR 3-11), 5263 participants died (crude mortality rate [MR] 13.7/1000 PYFU; 95%CI 13.4-14.1). Changing patterns of mortality were observed with AIDS as the most common cause of death between 1999- 2009 (n = 952, MR 4.2/1000 PYFU; 95%CI 4.0-4.5) and non-AIDS defining malignancy (NADM) from 2010 -2020 (n = 444, MR 2.8/1000 PYFU; 95%CI 2.5-3.1). In multivariable analysis, all-cause mortality declined over time (adjusted mortality rate ratio [aMRR] 0.97 per year; 95%CI 0.96, 0.98), mostly from 1999 through 2010 (aMRR 0.96 per year; 95%CI 0.95-0.97), and with no decline shown from 2011 through 2020 (aMRR 1·00 per year; 95%CI 0·96-1·05). Mortality due all known causes except NADM also declined over the entire follow-up period. CONCLUSION: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts decreased between 1999 and 2009 and was stable over the period from 2010 through 2020. The decline in mortality rates was not fully explained by improvements in immunologic-virologic status or other risk factors.

Longitudinal evaluation of SARS-CoV-2 T cell immunity over 2 years following vaccination and infection.

BACKGROUND: Within a year of the SARS-CoV-2 pandemic, vaccines inducing a robust humoral and cellular immune response were implemented worldwide. However, emergence of novel variants and waning vaccine induced immunity led to implementation of additional vaccine boosters. METHODS: This prospective study evaluated the temporal profile of cellular and serological responses in a cohort of 639 SARS-CoV-2 vaccinated participants, of whom a large proportion experienced a SARS-CoV-2 infection. All participants were infection naïve at the time of their first vaccine dose. Proportions of SARS-CoV-2 Spike-specific T cells were determined after each vaccine dose using the Activation Induced Markers (AIM) assay, while levels of circulating SARS-CoV-2 antibodies were determined by the Meso Scale serology assay. RESULTS: We found a significant increase in SARS-CoV-2 Spike-specific CD4+ and CD8+ T cell responses following the third dose of a SARS-CoV-2 mRNA vaccine as well as enhanced CD8+ T cell responses after the fourth dose. Further, increased age was associated with a poorer response. Finally, we observed that SARS-CoV-2 infection boosts both the cellular and humoral immune response, relative to vaccine-induced immunity alone. CONCLUSION: Our findings highlight the boosting effect on T cell immunity of repeated vaccine administration. The combination of multiple vaccine doses and SARS-CoV-2 infections maintains population T cell immunity although with reduced levels in the elderly.

Trends in underlying causes of death in allogeneic hematopoietic cell transplant recipients over the last decade.

OBJECTIVES: Improved survival after hematopoietic cell transplantation (HCT) and an increasingly comorbid transplant population may give rise to new trends in the causes of death. METHODS: This study includes all adult allogeneic HCT recipients transplanted at Rigshospitalet between January 1, 2010 and December 31, 2019. Underlying causes of death were determined using the Classification of Death Causes after Transplantation (CLASS) method. RESULTS: Among 802 HCT recipients, 289 died during the study period. The main causes of death were relapse (N = 133, 46.0%), graft-versus-host disease (GvHD) (N = 64, 22.1%) and infections (N = 35, 12.1%). Multivariable analyses showed that with increasing transplant calendar year, a decreased risk of all-cause mortality (HR 0.92, 95% CI 0.87-0.97) and death from GvHD (HR 0.87, 95% CI 0.78-0.97) was identified, but not for other specific causes. Standardized mortality ratios (SMRs) for all-cause mortality decreased from 23.8 (95% CI 19.1-28.5) to 18.4 (95% CI 15.0-21.9) for patients transplanted in 2010-2014 versus 2015-2019, while SMR for patients who died from GvHD decreased from 8.19 (95% CI 5.43-10.94) to 3.65 (95% CI 2.13-5.18). CONCLUSIONS: As risk of all-cause mortality and death from GvHD decreases, death from relapse remains the greatest obstacle in further improvement of survival after HCT.

Predicting type 2 diabetes risk before and after solid organ transplantation using polygenic scores in a Danish cohort.

Type 2 diabetes mellitus (T2DM) can be multifactorial where both genetics and environmental factors play a role. We aimed to investigate the use of polygenic risk scores (PRS) in the prediction of pre-transplant T2DM and post-transplant diabetes mellitus (PTDM) among solid organ transplant (SOT) patients. Using non-genetic risk scores alone; and the combination with PRS, separate logistic regression models were built and compared using receiver operator curves. Patients were assessed pre-transplant and in three post-transplant periods: 0-45, 46-365 and >365 days. A higher PRS was significantly associated with increased odds of pre-transplant T2DM. However, no improvement was observed for pre-transplant T2DM prediction when comparing PRS combined with non-genetic risk scores to using non-genetic risk scores alone. This was also true for predictions of PTDM in all three post-transplant periods. This study demonstrated that polygenic risk was only associated with the risk of T2DM among SOT recipients prior to transplant and not for PTDM. Combining PRS with a clinical model of non-genetic risk scores did not significantly improve the predictive ability, indicating its limited clinical utility in identifying patients at high risk for T2DM before transplantation, suggesting that non-genetic or different genetic factors may contribute to PTDM.

Donor Lymphocyte Infusion Is a Feasible Way to Improve Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Who Relapse after Allogeneic Stem Cell Transplantation.

INTRODUCTION: Donor lymphocyte infusion (DLI) is used to induce remission in patients who relapse after allogeneic stem cell transplantation (allo-HSCT). During the last decade, the hypomethylating agent Azacitidine has been used together with DLI for a synergistic graft-versus-leukemia (GVL) effect. Here we report results of DLI/Azacitidine treatment from a retrospective single-center study. METHODS: 50 AML/MDS patients treated for relapse after allo-HSCT between 2001 and 2020 with DLI at the Department of Hematology, at Rigshospitalet, Copenhagen University Hospital were included for analyses. A subgroup of patients who obtained complete remission (CR) after reinduction chemotherapy, received DLI in combination with low-dose (32 mg/m2) Azacitidine. RESULTS: Overall survival in all patients after DLI treatment was 59% at 2 years and 20% at 5 years. Relapse-free survival in patients in CR prior to DLI was 32% after 2 years and 7% after 5 years. In the DLI+low-dose-Azacitidine group, 5-years relapse-free survival was 40%. CONCLUSION: DLI remains an effective treatment in post-transplant relapse leaving one fifth of patients long-term survivors. Our results support the concomitant use of low-dose Azacitidine in the future use of DLI in order to enhance the GVL effect of donor lymphocytes.

Cross-sectional HIV and HCV cascades of care across the regions of Ukraine between 2019 and 2020: findings from the CARE cohort.

INTRODUCTION: Eastern Europe is facing major HIV and hepatitis C (HCV) epidemics, with many people living with HIV (PLHIV) and HIV/HCV coinfection living in Ukraine. Despite the previous progress towards care quality improvement, the ongoing war in Ukraine is disrupting HIV and HCV care. METHODS: We described an HIV cascade of care (CoC) in PLHIV from two clinical sites and an HCV CoC for anti-HCV-positive PLHIV from six sites in Ukraine, enrolled in the CARE cohort between 1 January 2019 and 1 June 2020. The cross-sectional HIV CoC and HCV CoC are described at study enrolment. RESULTS: Of 1028 PLHIV, 1014 (98.6%, 95% confidence interval [CI] 97.7-99.3) were on antiretroviral therapy (ART), and 876 (86.4% of those on ART, 95% CI 84.1-88.4) were virologically suppressed. Of 894 participants on ART >6 months, 90.8% (95% CI 88.7-92.6) were virologically suppressed (HIV-RNA <200 copies/ml). Of 2040 anti-HCV-positive PLHIV, 417 (20.4%, 95% CI 18.7-22.3) were ever tested for HCV-RNA prior to enrolment, ranging from 4.9% to 54.4% across sites, and 13.5% were currently HCV-RNA positive. One hundred and eighteen persons (7.3% of ever chronically infected) had received HCV treatment, and 25 persons (1.6% of ever chronically infected) were cured, with variations across sites (0%-7.5%). The site diagnosing 54.4% of people with chronic HCV was the only one providing free RNA testing for all anti-HCV-positive persons, while the intra-country differences in treatment coverage were driven by the number of available direct-acting antiviral (DAA) courses. CONCLUSIONS: Over 98% of PLHIV in care in both CARE sites in Ukraine were receiving ART, and the target of 90% virally suppressed was achieved in persons >6 months on ART. Only one of six HIV/HCV study sites tested over 50% anti-HCV-positive PLHIV for HCV-RNA and treated over 25% of eligible persons. While free HCV-RNA testing and DAA treatment are paramount to achieving HCV elimination targets, they remained a challenge in Ukraine in 2019-2020. The extent of the HIV and HCV care disruption during the war will be further assessed in the CARE cohort and compared with the pre-war findings.

SARS-CoV-2 vaccine-induced antibodies protect against Omicron breakthrough infection.

SARS-CoV-2 Omicron quickly spread globally, also in regions with high vaccination coverage, emphasizing the importance of exploring the immunological requirements for protection against Omicron breakthrough infection. The test-negative matched case-control study (N = 964) characterized Omicron breakthrough infections in triple-vaccinated individuals from the ENFORCE cohort. Within 60 days before a PCR test spike-specific IgG levels were significantly lower in cases compared to controls (GMR [95% CI] for BA.2: 0.83 [0.73-0.95], p = 0.006). Multivariable logistic regression showed significant associations between high antibody levels and lower odds of infection (aOR [95% CI] for BA.2 spike-specific IgG: 0.65 [0.48-0.88], p = 0.006 and BA.2 ACE2-blocking antibodies: 0.46 [0.30-0.69], p = 0.0002). A sex-stratified analysis showed more pronounced associations for females than males. High levels of vaccine-induced antibodies provide partial protection against Omicron breakthrough infections. This is important knowledge to further characterize a threshold for protection against new variants and to estimate the necessity and timing of booster vaccination.

Omicron Variant-Specific Serological Imprinting Following BA.1 or BA.4/5 Bivalent Vaccination and Previous SARS-CoV-2 Infection: A Cohort Study.

BACKGROUND: Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outpaces monovalent vaccine cross-protection to new viral variants. Consequently, bivalent coronavirus disease 2019 (COVID-19) vaccines including Omicron antigens were developed. The contrasting immunogenicity of the bivalent vaccines and the impact of prior antigenic exposure on new immune imprinting remains to be clarified. METHODS: In the large prospective ENFORCE cohort, we quantified spike-specific antibodies to 5 Omicron variants (BA.1 to BA.5) before and after BA.1 or BA.4/5 bivalent booster vaccination to compare Omicron variant-specific antibody inductions. We evaluated the impact of previous infection and characterized the dominant antibody responses. RESULTS: Prior to the bivalent fourth vaccine, all participants (N = 1697) had high levels of Omicron-specific antibodies. Antibody levels were significantly higher in individuals with a previous polymerase chain reaction positive (PCR+) infection, particularly for BA.2-specific antibodies (geometric mean ratio [GMR] 6.79, 95% confidence interval [CI] 6.05-7.62). Antibody levels were further significantly boosted in all individuals by receiving either of the bivalent vaccines, but greater fold inductions to all Omicron variants were observed in individuals with no prior infection. The BA.1 bivalent vaccine generated a dominant response toward BA.1 (adjusted GMR 1.31, 95% CI 1.09-1.57) and BA.3 (1.32, 1.09-1.59) antigens in individuals with no prior infection, whereas the BA.4/5 bivalent vaccine generated a dominant response toward BA.2 (0.87, 0.76-0.98), BA.4 (0.85, 0.75-0.97), and BA.5 (0.87, 0.76-0.99) antigens in individuals with a prior infection. CONCLUSIONS: Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen. Importantly, both bivalent vaccines induce high levels of Omicron variant-specific antibodies, suggesting broad cross-protection of Omicron variants.

Association of Self-reported Systemic Reactions Following SARS-CoV-2 Vaccination With Immunological Response in the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE).

Background: Side effects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are a key concern contributing to vaccine hesitancy, but more individuals may be encouraged if SARS-CoV-2 vaccines were known to lead to a stronger immune response. Methods: Included were adult participants from the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE) who completed a questionnaire to assess systemic reactions following SARS-CoV-2 vaccination (BTN162b2, mRNA-1273, ChAdOx1) and had SARS-CoV-2 spike immunoglobulin G (IgG) levels measured at baseline and post-vaccine. A symptom score was developed to measure severity of systemic adverse reactions (+1 for each moderate, +2 for each severe). Post-vaccination SARS-CoV-2 spike IgG levels were compared between participants with different scores using multivariable linear regression. Results: A total of 6528 participants were included (56.3% females; median age [interquartile range], 64 [54-75] years). After the first vaccination, no association was found between symptom score and post-vaccine dose spike IgG level (P = .575). Following the second vaccination, significantly higher spike IgG levels were observed according to higher symptom scores (P < .001); adjusted geometric mean ratios were 1.16 (95% CI, 1.04-1.30), 1.24 (95% CI, 1.09-1.41), 1.25 (95% CI, 1.06-1.46), and 1.21 (95% CI, 1.08-1.35), for scores of 2, 3, 4, and ≥5, respectively, compared with a score of 0. After adjustment for pre-vaccine dose spike IgG, this association was attenuated. Conclusions: An association was found between more severe adverse reactions and stronger antibody response after the second vaccination but not the first, likely attributed to higher levels of preexisting immunity gained from response to first vaccination. Regardless of side effects, most people experienced an effective immune response following vaccination.

Impact of age and comorbidities on SARS-CoV-2 vaccine-induced T cell immunity.

BACKGROUND: Older age and chronic disease are important risk factors for developing severe COVID-19. At population level, vaccine-induced immunity substantially reduces the risk of severe COVID-19 disease and hospitalization. However, the relative impact of humoral and cellular immunity on protection from breakthrough infection and severe disease is not fully understood. METHODS: In a study cohort of 655 primarily older study participants (median of 63 years (IQR: 51-72)), we determined serum levels of Spike IgG antibodies using a Multiantigen Serological Assay and quantified the frequency of SARS-CoV-2 Spike-specific CD4 + and CD8 + T cells using activation induced marker assay. This enabled characterization of suboptimal vaccine-induced cellular immunity. The risk factors of being a cellular hypo responder were assessed using logistic regression. Further follow-up of study participants allowed for an evaluation of the impact of T cell immunity on breakthrough infections. RESULTS: We show reduced serological immunity and frequency of CD4 + Spike-specific T cells in the oldest age group (≥75 years) and higher Charlson Comorbidity Index (CCI) categories. Male sex, age group ≥75 years, and CCI > 0 is associated with an increased likelihood of being a cellular hypo-responder while vaccine type is a significant risk factor. Assessing breakthrough infections, no protective effect of T cell immunity is identified. CONCLUSIONS: SARS-CoV-2 Spike-specific immune responses in both the cellular and serological compartment of the adaptive immune system increase with each vaccine dose and are progressively lower with older age and higher prevalence of comorbidities. The findings contribute to the understanding of the vaccine response in individuals with increased risk of severe COVID-19 disease and hospitalization.

Vaccination has proven very effective in protecting against severe disease and hospitalization of people with COVID-19, the disease caused by SARS-CoV-2. It is still unclear, however, how the different components of the immune system respond to SARS-CoV-2 vaccination and protect from infection and severe disease. Two of the most predominant components of the immune system are specialized proteins and cells. The proteins circulate in the blood and help clear the virus by binding to it, while the cells either kill the virus or help other cells to produce more antibodies. Here, we examined the response of these two components to the SARS-CoV-2 vaccine in 655 Danish citizens. The response of both components was lower in people over 75 years old and with other diseases. These findings help in understanding the immune responses following SARS-CoV-2 vaccination in people at increased risk of severe symptoms of COVID-19.

Incidence and risk factors for suicide, death due to substance use, and violent/accidental death in people with HIV.

OBJECTIVE: Deaths due to suicide, substance use and violence/accident may reflect similar risk factors and overlap in their classification. This study aimed to investigate incidence and risk factors of mortality among people with HIV (PWH) due to these three related causes. DESIGN: Prospectively collected data from PWH at least 18 years old and under active follow-up in the EuroSIDA study from 2007 to 2019 were analysed. METHODS: Cause-specific Cox regression analysis was used to assess risk factors. RESULTS: A total of 17 881 participants were included, comprising 149 327 person-years of follow-up (PYFU). Forty participants died by suicide {incidence rate [IR] [95% confidence interval (CI)]: 0.3/1000 PYFU (0.2, 0.4)} 93 from substance use [IR (95% CI): 0.6/1000 PYFU (0.5, 0.8)], and 57 by violence/accident [IR (95% CI): 0.4/1000 PYFU (0.3, 0.5)]. An AIDS diagnosis within the last 12 months was associated with nine-fold increased risk of suicide vs. no history of AIDS [adjusted hazard ratio (aHR): 9.06; 95% CI: 2.07, 39.7]. Male gender was associated with double the risk of violent/accidental death (aHR: 2.28; 95% CI: 1.09, 4.78). PWH in Eastern Europe and those who acquired HIV by injection drug use (IDU) demonstrated a greater risk of death due to substance use or violence/accident. CONCLUSIONS: The association between a recent diagnosis of AIDS and suicide highlights a critical period for intervention. HIV infection acquired through IDU demonstrated an expected relationship with death due to substance use and violent/accidental deaths. Increased risk of death due to substance use and violence/accident in Eastern Europe demands investigation into specific differences that may drive that association.

Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV.

INTRODUCTION: Identifying genetic factors that influence HIV-pathogenesis is critical for understanding disease pathways. Previous studies have suggested a role for the human gene ten-eleven methylcytosine dioxygenase 2 (TET2) in modulating HIV-pathogenesis. METHODS: We assessed whether genetic variation in TET2 was associated with markers of HIV-pathogenesis using both gene level and single nucleotide polymorphism (SNP) level association in 8512 HIV-positive persons across five clinical trial cohorts. RESULTS: Variation at both the gene and SNP-level of TET2 was found to be associated with levels of HIV viral load (HIV-VL) consistently in the two cohorts that recruited antiretroviral-naïve participants. The SNPs occurred in two clusters of high linkage disequilibrium (LD), one associated with high HIV-VL and the other low HIV-VL, and were predominantly found in Black participants. CONCLUSION: Genetic variation in TET2 was associated with HIV-VL in two large antiretroviral therapy (ART)-naive clinical trial cohorts. The role of TET2 in HIV-pathogenesis warrants further investigation.

Increased incidence rates of positive blood cultures shortly after chemotherapy compared to radiotherapy among individuals treated for solid malignant tumours.

BACKGROUND: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated. METHODS: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated. FINDINGS: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified. INTERPRETATION: PBCs are not common, but when they occur, mortality is high.

Readmissions, Postdischarge Mortality, and Sustained Recovery Among Patients Admitted to Hospital With Coronavirus Disease 2019 (COVID-19).

BACKGROUND: Many interventional in-patient coronavirus disease 2019 (COVID-19) trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization. METHODS: Among adults hospitalized with COVID-19 in eastern Denmark from 18 March 2020-12 January 2021 we assessed all-cause mortality, recovery, and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days. RESULTS: Among 3386 patients included in the study, 2796 (82.6%) reached recovery and 2600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted and 289 (10.3%) died. Overall, the median time to recovery was 6 days (interquartile range [IQR]: 3-10), and 19 days (IQR: 11-33) among patients in intensive care in the first 2 days of admission. CONCLUSIONS: Postdischarge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28-day follow-up period may be too short for the critically ill.

Cohort Profile:The Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 vaccines (ENFORCE).

PURPOSE: The ENFORCE cohort is a national Danish prospective cohort of adults who received a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine as part of the Danish National SARS-CoV-2 vaccination programme. It was designed to investigate the long-term effectiveness, safety and durability of SARS-CoV-2 vaccines used in Denmark. PARTICIPANTS: A total of 6943 adults scheduled to receive a SARS-CoV-2 vaccine in the Danish COVID-19 vaccination programme were enrolled in the study prior to their first vaccination. Participants will be followed for a total of 2 years with five predetermined follow-up visits and additional visits in relation to any booster vaccination. Serology measurements are performed after each study visit. T-cell immunity is evaluated at each study visit for a subgroup of 699 participants. Safety information is collected from participants at visits following each vaccination. Data on hospital admissions, diagnoses, deaths and SARS-CoV-2 PCR results are collected from national registries throughout the study period. The median age of participants was 64 years (IQR 53-75), 56.6% were women and 23% were individuals with an increased risk of a serious course of COVID-19. A total of 340 (4.9%) participants tested positive for SARS-CoV-2 spike IgG at baseline. FINDINGS TO DATE: Results have been published on risk factors for humoral hyporesponsiveness and non-durable response to SARS-CoV-2 vaccination, the risk of breakthrough infections at different levels of SARS-CoV-2 spike IgG by viral variant and on the antibody neutralising capacity against different SARS-CoV-2 variants following primary and booster vaccinations. FUTURE PLANS: The ENFORCE cohort will continuously generate studies investigating immunological response, effectiveness, safety and durability of the SARS-CoV-2 vaccines. TRIAL REGISTRATION NUMBER: NCT04760132.

Chest x-ray imaging score is associated with severity of COVID-19 pneumonia: the MBrixia score.

Spatial resolution in existing chest x-ray (CXR)-based scoring systems for coronavirus disease 2019 (COVID-19) pneumonia is low, and should be increased for better representation of anatomy, and severity of lung involvement. An existing CXR-based system, the Brixia score, was modified to increase the spatial resolution, creating the MBrixia score. The MBrixia score is the sum, of a rule-based quantification of CXR severity on a scale of 0 to 3 in 12 anatomical zones in the lungs. The MBrixia score was applied to CXR images from COVID-19 patients at a single tertiary hospital in the period May 4th-June 5th, 2020. The relationship between MBrixia score, and level of respiratory support at the time of performed CXR imaging was investigated. 37 hospitalized COVID-19 patients with 290 CXRs were identified, 22 (59.5%) were admitted to the intensive care unit and 10 (27%) died during follow-up. In a Poisson regression using all 290 MBrixia scored CXRs, a higher MBrixia score was associated with a higher level of respiratory support at the time of performed CXR. The MBrixia score could potentially be valuable as a quantitative surrogate measurement of COVID-19 pneumonia severity, and future studies should investigate the score's validity and capabilities of predicting clinical outcomes.

Comparison of vaccine-induced antibody neutralization against SARS-CoV-2 variants of concern following primary and booster doses of COVID-19 vaccines.

The SARS-CoV-2 pandemic has, as of July 2022, infected more than 550 million people and caused over 6 million deaths across the world. COVID-19 vaccines were quickly developed to protect against severe disease, hospitalization and death. In the present study, we performed a direct comparative analysis of four COVID-19 vaccines: BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), ChAdOx1 (Oxford/AstraZeneca) and Ad26.COV2.S (Johnson & Johnson/Janssen), following primary and booster vaccination. We focused on the vaccine-induced antibody-mediated immune response against multiple SARS-CoV-2 variants: wildtype, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta) and B.1.1.529 (Omicron). The analysis included the quantification of total IgG levels against SARS-CoV-2 Spike, as well as the quantification of antibody neutralization titers. Furthermore, the study assessed the high-throughput ACE2 competition assay as a surrogate for the traditional pseudovirus neutralization assay. The results demonstrated marked differences in antibody-mediated immune responses. The lowest Spike-specific IgG levels and antibody neutralization titers were induced by one dose of the Ad26.COV2.S vaccine, intermediate levels by two doses of the BNT162b2 vaccine, and the highest levels by two doses of the mRNA-1273 vaccine or heterologous vaccination of one dose of the ChAdOx1 vaccine and a subsequent mRNA vaccine. The study also demonstrated that accumulation of SARS-CoV-2 Spike protein mutations was accompanied by a marked decline in antibody neutralization capacity, especially for B.1.1.529. Administration of a booster dose was shown to significantly increase Spike-specific IgG levels and antibody neutralization titers, erasing the differences between the vaccine-induced antibody-mediated immune response between the four vaccines. The findings of this study highlight the importance of booster vaccines and the potential inclusion of future heterologous vaccination strategies for broad protection against current and emerging SARS-CoV-2 variants.

Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections.

SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21-28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15-0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron.

Changes in body mass index and clinical outcomes after initiation of contemporary antiretroviral regimens.

BACKGROUND: Weight gain is becoming increasingly prevalent amongst people with HIV (PWH) receiving contemporary antiretroviral treatment. We investigated BMI changes and clinical impact in a large prospective observational study. METHODS: PWH aged ≥18 years were included who started a new antiretroviral (baseline) during 2010-2019 with baseline and ≥1 follow-up BMI assessment available. Rates of clinical outcomes (cardiovascular disease [CVD], malignancies, diabetes mellitus [DM] and all-cause mortality) were analysed using Poisson regression to assess effect of time-updated BMI changes (>1 kg/m 2 decrease, ±1 kg/m 2 stable, >1 kg/m 2 increase), lagged by 1-year to reduce reverse causality. Analyses were adjusted for baseline BMI plus key confounders including antiretroviral exposure. RESULTS: 6721 PWH were included; 72.3% were male, median age 48 years (interquartile range [IQR] 40-55). At baseline, 8.4% were antiretroviral-naive, and 5.0% were underweight, 59.7% healthy weight, 27.5% overweight, and 7.8% were living with obesity. There was an 8.2% increase in proportion of overweight and 4.8% in obesity over the study period (median follow-up 4.4 years [IQR 2.6-6.7]).100 CVDs, 149 malignancies, 144 DMs, and 257 deaths were observed with incidence rates 4.4, 6.8, 6.6, 10.6 per 1000 person-years of follow-up, respectively. Compared to stable BMI, >1 kg/m 2 increase was associated with increased risk of DM (adjusted incidence rate ratio [IRR]: 1.96, 95% confidence interval [CI]: 1.36-2.80) and >1 kg/m 2 decrease with increased risk of death (adjusted IRR: 2.33, 95% CI: 1.73-3.13). No significant associations were observed between BMI changes and CVD or malignancies. CONCLUSIONS: A BMI increase was associated with DM and a decrease associated with death.