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

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 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 IV 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 post-1(st) vaccination. Non-durable vaccine-response was defined as day 90 responders that no longer had significant responses by day 180. RESULTS: Of 6544 participants completing two vaccine doses (median age 64, interquartile range:54–75), 3654 (55.8%) received BTN162b2, 2472 (37.8%) mRNA-1273, and 418 (6.4%) ChAdOx1 followed by a 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 hypo-responsiveness and lack of durable response were 5.0% and 12.1% for Spike IgG; 12.7% and 39.6% for Spike-ACE2-receptor-blocking antibody levels, respectively. Male sex, vaccine type and number of co-morbidities were associated with all four outcomes. Additionally, age >=75y was associated with hypo-responsiveness for Spike-ACE2-receptor-blocking antibodies (adjusted odds-ratio:1.59, 95% confidence interval:1.25–2.01) but not for Spike IgG. CONCLUSIONS: Comorbidity, male sex and vaccine type were risk factors for hypo-responsiveness and non-durable response to COVID-19 vaccination. The functional activity of vaccine-induced antibodies declined with increasing age and had waned to pre-2(nd) vaccination levels for most individuals after 6 months

Site of infection and mortality in patients with severe sepsis or septic shock:A cohort study of patients admitted to a Danish general intensive care unit

<p><b>Background:</b> The search for the site of infection has high priority in patients with severe sepsis and septic shock. However, it is questionable whether mortality is associated with the specific site of infection in patients admitted to an intensive care unit (ICU). Therefore, the 30-day and 90-day mortalities in ICU patients admitted with suspected or confirmed community-acquired infection were studied.</p> <p><b>Methods:</b> A retrospective cohort study was conducted, including all adult patients admitted to a multi-specialty tertiary ICU with severe sepsis or septic shock from November 2008 to October 2010. The site of infection was classified according to criteria set for healthcare associated infections and infections in the acute care setting by Centers for Disease Control and Prevention (CDC). Kaplan–Meier curves and Poisson regression analysis were used to evaluate the association between site of infection and 30- and 90-day all-cause mortality, adjusting for age, sex and comorbidities.</p> <p><b>Results:</b> Three hundred and eighty-eight patients were included. One or more comorbidities were present in 76% of patients. Across all sites of infection, there were more patients with septic shock than patients with severe sepsis. The most frequent site of infection was pneumonia, followed by gastrointestinal infection. Urinary tract infection was found to be an independent predictor of mortality among septic ICU patients when adjusting for sex, age and comorbidities.</p> <p><b>Conclusions:</b> The results suggest that identification of correct site of infection is important in the management of severe sepsis and septic shock.</p

Site of infection and mortality in patients with severe sepsis or septic shock. A cohort study of patients admitted to a Danish general intensive care unit

Background: The search for the site of infection has high priority in patients with severe sepsis and septic shock. However, it is questionable whether mortality is associated with the specific site of infection in patients admitted to an intensive care unit (ICU). Therefore, the 30-day and 90-day mortalities in ICU patients admitted with suspected or confirmed community-acquired infection were studied. Methods: A retrospective cohort study was conducted, including all adult patients admitted to a multi-specialty tertiary ICU with severe sepsis or septic shock from November 2008 to October 2010. The site of infection was classified according to criteria set for healthcare associated infections and infections in the acute care setting by Centers for Disease Control and Prevention (CDC). Kaplan–Meier curves and Poisson regression analysis were used to evaluate the association between site of infection and 30- and 90-day all-cause mortality, adjusting for age, sex and comorbidities. Results: Three hundred and eighty-eight patients were included. One or more comorbidities were present in 76% of patients. Across all sites of infection, there were more patients with septic shock than patients with severe sepsis. The most frequent site of infection was pneumonia, followed by gastrointestinal infection. Urinary tract infection was found to be an independent predictor of mortality among septic ICU patients when adjusting for sex, age and comorbidities. Conclusions: The results suggest that identification of correct site of infection is important in the management of severe sepsis and septic shock

Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection (NCT03041012). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence

Early intervention with 3BNC117 and romidepsin at antiretroviral treatment initiation in people with HIV-1: a phase 1b/2a, randomized trial

Attempts to reduce the human immunodeficiency virus type 1 (HIV-1) reservoir and induce antiretroviral therapy (ART)-free virologic control have largely been unsuccessful. In this phase 1b/2a, open-label, randomized controlled trial using a four-group factorial design, we investigated whether early intervention in newly diagnosed people with HIV-1 with a monoclonal anti-HIV-1 antibody with a CD4-binding site, 3BNC117, followed by a histone deacetylase inhibitor, romidepsin, shortly after ART initiation altered the course of HIV-1 infection (NCT03041012). The trial was undertaken in five hospitals in Denmark and two hospitals in the United Kingdom. The coprimary endpoints were analysis of initial virus decay kinetics and changes in the frequency of CD4+ T cells containing intact HIV-1 provirus from baseline to day 365. Secondary endpoints included changes in the frequency of infected CD4+ T cells and virus-specific CD8+ T cell immunity from baseline to day 365, pre-ART plasma HIV-1 3BNC117 sensitivity, safety and tolerability, and time to loss of virologic control during a 12-week analytical ART interruption that started at day 400. In 55 newly diagnosed people (5 females and 50 males) with HIV-1 who received random allocation treatment, we found that early 3BNC117 treatment with or without romidepsin enhanced plasma HIV-1 RNA decay rates compared to ART only. Furthermore, 3BNC117 treatment accelerated clearance of infected cells compared to ART only. All groups had significant reductions in the frequency of CD4+ T cells containing intact HIV-1 provirus. At day 365, early 3BNC117 + romidepsin was associated with enhanced HIV-1 Gag-specific CD8+ T cell immunity compared to ART only. The observed virological and immunological effects of 3BNC117 were most pronounced in individuals whose pre-ART plasma HIV-1 envelope sequences were antibody sensitive. The results were not disaggregated by sex. Adverse events were mild to moderate and similar between the groups. During a 12-week analytical ART interruption among 20 participants, 3BNC117-treated individuals harboring sensitive viruses were significantly more likely to maintain ART-free virologic control than other participants. We conclude that 3BNC117 at ART initiation enhanced elimination of plasma viruses and infected cells, enhanced HIV-1-specific CD8+ immunity and was associated with sustained ART-free virologic control among persons with 3BNC117-sensitive virus. These findings strongly support interventions administered at the time of ART initiation as a strategy to limit long-term HIV-1 persistence