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.

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.

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.

The cascade of care in tuberculosis infection screening and management in newly arrived refugees in Aarhus, Denmark.

BACKGROUND: Screening for tuberculosis (TB) disease and infection is often a part of health screening programs offered to refugees, but the yield of screening varies and losses along the steps from screening to treatment completion was reported. METHODS: A retrospective cohort study was performed investigating a newly arrived refugee population offered a systematic refugee health assessment in Aarhus, Denmark. Data was collected on screening, referral, diagnosis and treatment for TB disease and infection. RESULTS: Among both adults and children IGRA positivity was associated with origin in a high TB incidence country and increasing age. The number needed to screen (NNS) to find one case of TB infection was 7 among adult refugees and 19 among children, while NNS for TB disease was 266 and 164 respectively. The proportion of the eligible population with a valid result was 78.1% for adults and 71.3% for children, while 43.1% and 50% of adults and children with presumed TB infection completed preventive treatment. DISCUSSION: Screening for TB disease and infection among refugees in Aarhus had a high yield in terms of diagnosis, however significant losses were seen during screening, follow-up and preventive treatment completion.

Characteristics associated with serological COVID-19 vaccine response and durability in an older population with significant comorbidity: the Danish Nationwide ENFORCE Study.

OBJECTIVES: To identify individual characteristics associated with serological COVID-19 vaccine responsiveness and the durability of vaccine-induced antibodies. METHODS: Adults without history of SARS-CoV-2 infection from the Danish population scheduled for SARS-CoV-2 vaccination were enrolled in this parallel group, phase 4 study. SARS-CoV-2 Spike IgG and Spike-ACE2-receptor-blocking antibodies were measured at days 0, 21, 90, and 180. Vaccine responsiveness was categorized according to Spike IgG and Spike-ACE2-receptor-blocking levels at day 90 after first vaccination. Nondurable vaccine response was defined as day-90 responders who no longer had significant responses by day 180. RESULTS: Of 6544 participants completing two vaccine doses (median age 64 years; interquartile range: 54-75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by an mRNA vaccine. Levels of both types of antibodies increased from baseline to day 90 and then decreased to day 180. The decrease was more pronounced for levels of Spike-ACE2-receptor-blocking antibodies than for Spike IgG. Proportions with vaccine hyporesponsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG and 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type, and number of comorbidities were associated with all four outcomes. Additionally, age ≥75 years was associated with hyporesponsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds ratio: 1.59; 95% confidence interval: 1.25-2.01) but not for Spike IgG. DISCUSSION: Comorbidity, male sex, and vaccine type were risk factors for hyporesponsiveness and nondurable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-second-vaccination levels for most individuals after 6 months.

A cohort study of the long-term outcome of latent tuberculosis infection among socially marginalized people in a low-incidence country.

BACKGROUND: Tuberculosis (TB) prevalence is high among socially marginalized citizens in Denmark, and management of latent TB infection (LTBI) may be part of preventing new cases. Patients with LTBI are offered either preventive treatment (TPT) or follow-up chest x-rays, but knowledge about the long-term outcome in terms of active TB is sparse. METHODS: We performed a retrospective cohort study investigating the long-term outcomes for socially marginalized citizens who were diagnosed with LTBI or who had a positive interferon-gamma release assay (IGRA) but were lost to follow-up. Information on TB examinations, diagnostics, and treatment along with data on death were gathered from medical records from the date of positive IGRA to February 1, 2021. RESULTS: We identified 119 patients with LTBI, 18 of which (15.1%) were diagnosed with TB during the follow-up period (mean, 4.5 years). TPT was completed by 36.1% and the TB incidence rate ratio of those completing TPT to those who did not was 0.78 (confidence interval, 0.25-2.17; P =.6). Of the patients with TB, 16 of 18 achieved treatment success. CONCLUSION: High rates of TB development are found among socially marginalized citizens with LTBI. Overall incidence of TB was not significantly reduced by administration of TPT, although TB did not develop in the first 2 years following TPT.

Lot-to-lot consistency, safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in healthy adults aged ≥50 years: A randomized phase 3 trial (PNEU-TRUE).

BACKGROUND: Older adults are at risk of pneumococcal disease and associated morbidity and mortality. This phase 3 study (V114-020) assessed lot-to-lot consistency across safety and immunogenicity outcomes for V114, a 15-valent pneumococcal conjugate vaccine (PCV), in healthy adults aged ≥ 50 years. METHODS: Adults were randomized in a 3:3:3:1 ratio to receive a single dose of one of three lots of V114 or 13-valent PCV (PCV13), stratified by age (50-64 years, 65-74 years, and ≥ 75 years). Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were evaluated at baseline (Day 1) and 30 days post-vaccination. Non-serious and serious adverse events (AEs) were evaluated post-vaccination through 14 days and Month 6, respectively. RESULTS: Of 2340 participants enrolled, 2282 (97.5%) completed the study. Proportions of participants experiencing ≥ 1 AE were 81.0%, 77.4%, and 78.0% for V114 lots 1, 2, and 3, respectively. Comparison of V114 combined lots with PCV13 showed that proportions of participants experiencing AEs, solicited AEs, and serious AEs were comparable for both vaccines, with the exception of injection-site pain (more frequently reported with V114). OPA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) at 30 days post-vaccination were comparable across V114 lots, and all lots met predefined equivalence criteria for all 15 vaccine serotypes (lower and upper limits of the 95% confidence intervals of serotype-specific OPA GMT ratios for all possible pairwise comparisons across the three lots were within the equivalence margin of 0.5-2.0). Serotype-specific OPA GMTs and IgG GMCs were comparable in the V114 combined lots and PCV13 groups for the 13 shared serotypes and higher in the V114 group for serotypes unique to V114 (22F and 33F). CONCLUSIONS: V114 is well tolerated with a consistent safety profile and immune response across manufacturing lots. CLINICAL TRIALS REGISTRATION: NCT03950856 (www.clinicaltrials.gov); 2018-004266-33 (EudraCT).

Tuberculosis incidence and mortality in people living with human immunodeficiency virus: a Danish nationwide cohort study.

OBJECTIVES: To explore changes over time in the epidemiology of tuberculosis (TB) in Denmark in people living with human immunodeficiency virus (HIV) (PLWH). METHODS: In this nationwide, population-based cohort study we included all adult PLWH from the Danish HIV Cohort Study (1995-2017) without previous TB. We estimated TB incidence rate (IR), all-cause mortality rate (MR), associated risk and prognostic factors using Poisson regression. RESULTS: Among 6982 PLWH (73 596 person-years (PY)), we observed 217 TB events (IR 2.9/1000 PY, 95% CI 2.6-3.4: IR 6.7, 95% CI 5.7-7.9 among migrants and IR 1.4, 95% CI 1.1-1.7 among Danish-born individuals; p < 0.001). The IR of concomitant HIV/TB remained high and unchanged over time. The IR of TB diagnosed >3 months after HIV diagnosis declined with calendar time, longer time from HIV diagnosis, and CD4 cell recovery. Independent TB risk factors were African/Asian/Greenland origin (adjusted incidence rate ratio (aIRR) 5.2, 95% CI 3.5-7.6, aIRR 6.5, 95% CI 4.2-10.0, aIRR 7.0, 95% CI 3.4-14.6, respectively), illicit drug use (aIRR 6.9, 95% CI 4.2-11.2), CD4 <200 cells/µL (aIRR 2.7, 95% CI 2.0-3.6) and not receiving antiretroviral therapy (aIRR 3.7, 95% CI 2.5-5.3). Fifty-five patients died (MR 27.9/1000 PY, 95% CI 21.4-36.3), with no improvement in mortality over time. Mortality prognostic factors were Danish-origin (adjusted mortality rate ratio (aMRR) 2.3, 95% CI 1.3-4.3), social burden (aMRR 3.9, 95% CI 2.2-7.0), CD4 <100 cells/µL at TB diagnosis (aMRR 2.6, 95% CI 1.3-4.9), TB diagnosed >3 months after HIV versus concomitant diagnosis (aMRR 4.3, 95% CI 2.2-8.7) and disseminated TB (aMRR 3.3, 95% CI 1.1-9.9). CONCLUSION: Late HIV presentation with concomitant TB remains a challenge. Declining TB rates in PLWH were observed over time and with CD4 recovery, highlighting the importance of early and successful antiretroviral therapy. However, MR remained high. Our findings highlight the importance of HIV and TB screening strategies and treatment of latent TB in high-risk groups.

High yield from repeated testing for tuberculosis among high-risk citizens in Denmark.

BACKGROUND: Screening for TB (tuberculosis) among socially marginalized citizens has been implemented in many urban areas in countries with a low incidence of TB, including Denmark. This study aims to describe the findings of the screening programs for TB and latent tuberculosis (LTBI) used in the western part of Denmark in the period 2014-2019. METHODS: Data was collected retrospectively on test results from interferon-gamma release assays (IGRA), spot sputum tests and chest X-rays performed as part of TB and LTBI screening among 1024 socially marginalized citizens in urban areas of western Denmark in 2014-2019. RESULTS: The overall TB incidence was 2148/100.000 and number needed to screen to find one TB case was 39. The incidence of LTBI in the group screened using IGRA was 17.500/100.000. TB incidence when using spot sputum test was 2.5, while TB incidence when using IGRA as the primary screening test was 2.7. In total, 38.9% of TB diagnoses were obtained after the second or third round of screening. CONCLUSION: We demonstrated a high incidence of TB and LTBI among socially marginalized citizens in Denmark. Screening with spot sputum testing and IGRA generated comparable results in diagnosing TB in this setting.

Incidence, clinical presentation, and outcome of HIV-1-associated cryptococcal meningitis during the highly active antiretroviral therapy era: a nationwide cohort study.

BACKGROUND: Human immunodeficiency virus (HIV) infection with advanced immunosuppression predisposes to cryptococcal meningitis (CM). We describe the incidence, clinical presentation, and outcome of CM in HIV-infected individuals during the highly active antiretroviral therapy (HAART) era. METHODS: A nationwide, population-based cohort of HIV-infected individuals was used to estimate incidence and mortality of CM including risk factors. A description of neurological symptoms of CM at presentation and follow-up in the study period 1995-2014 was included in this study. RESULTS: Among 6,351 HIV-infected individuals, 40 were diagnosed with CM. The incidence rates were 3.7, 1.8, and 0.3 per 1000 person-years at risk in 1995-1996, 1997-1999, and 2000-2014, respectively. Initiation of HAART was associated with decreased risk of acquiring CM [incidence rate ratio (IRR), 0.1 (95% CI, 0.05-0.22)]. African origin was associated with increased risk of CM [IRR, 2.05 (95% CI, 1.00-4.20)]. The main signs and symptoms at presentation were headache, cognitive deficits, fever, neck stiffness, nausea, and vomiting. All individuals diagnosed with CM had a CD4+ cell count <200 cells/µl [median 26; interquartile range (IQR), 10-50)]. Overall, mortality following CM was high and mortality in the first 4 months has not changed substantially over time. However, individuals who survived generally had a favorable prognosis, with 86% (18/21) returning to the pre-CM level of activity. CONCLUSION: The incidence of HIV-associated CM has decreased substantially after the introduction of HAART. To further decrease CM incidence and associated mortality, early HIV diagnosis and HAART initiation seems crucial.

Incidence, presentation and outcome of toxoplasmosis in HIV infected in the combination antiretroviral therapy era.

BACKGROUND: HIV-associated incidence and prognosis of cerebral toxoplasmosis (CTX) is not well established during later years. METHODS: From the Danish HIV Cohort Study, we identified 6325 HIV-infected individuals. We assessed incidence, mortality, predictive and prognostic factors of CTX during the pre-combination antiretroviral therapy (pre-cART; 1995-1996) and cART-era (1997-2014). Adjusted incidence rate ratios (aIRR), mortality rate ratios (aMRR) and 95% confidence intervals (CI) were assessed using Poisson regression analysis. RESULTS: CTX IR was 1.17/1000 PYR (95% CI 0.93-1.47). We observed no change in CTX-risk in the first year after HIV-diagnosis, but a substantial reduction in mortality in the first 3 months after CTX diagnosis when comparing the cART-era to the pre-cART-era; {(aIRR: 0.79; 95% CI: 0.37-1.72) (aMRR: 0.15; 95% CI: 0.06-0.38)}. For individuals surviving the first year after HIV-diagnosis or the first 3 months after CTX-diagnosis, IRR and MRR had declined to minimal levels {(aIRR: 0.06; 95% CI: 0.03-0.10); (aMRR: 0.02; 95% CI: 0.01-0.05)}. Three years after CTX-diagnosis 30% of the patients still had neurological deficits. CONCLUSION: Although, CTX remains an important cause of morbidity and mortality in the cART-era, with high prevalence of neurological sequelae, incidence and mortality has largely declined, especially among those surviving the first year after diagnosis.

Latent tuberculosis infection is prevalent among socially marginalised citizens in Aarhus, Denmark.

INTRODUCTION: Even in low-incidence countries, tuberculosis (TB) is common among socially marginalised people. Latent tuberculosis infection (LTBI) comprises a reservoir for future disease, and screening for LTBI and TB in these groups aids in the prevention and early detection of TB. METHODS: We performed a screening for LTBI with interferon gamma release assay (IGRA) testing, and TB screening with sputum smear examination at four shelters and four additional locations in a Danish urban area. Additionally, shelter volunteers were offered examination. RESULTS: A total of 145 subjects were tested; 124 with sputum smear and 100 with IGRA. Overall, 13 (13%) had LTBI, and one (0.8%) had smear-negative, culture-positive, non-cavitating TB. Among 107 socially marginalised citizens, persons of Greenlandic origin had significantly more LTBI (40.0%) than Danish subjects (9.1%) (odds ratio (OR) = 6.67 (range: 1.55-28.63)), and other ethnicities had an intermediate prevalence of LTBI (18.2%) (OR versus Danish subjects = 2.22 (range: 0.35-14.06)). A total of 38 shelter volunteers were also included; IGRA was performed in 30 of those and one (3.33%) had LTBI. CONCLUSIONS: Our results confirm that a screening approach may reveal early cases of active TB. LTBI is common among the socially marginalised people, but varies substantially with ethnic origin. FUNDING: T-spot.TB kits were provided by Oxford Immunotec. TRIAL REGISTRATION: not relevant.