ABSTRACT
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.
Subject(s)
Epigenomics , Immunity/genetics , Influenza Vaccines/genetics , Influenza Vaccines/immunology , Single-Cell Analysis , Transcription, Genetic , Vaccination , Adolescent , Adult , Anti-Bacterial Agents/pharmacology , Antigens, CD34/metabolism , Antiviral Agents/pharmacology , Cellular Reprogramming , Chromatin/metabolism , Cytokines/biosynthesis , Drug Combinations , Female , Gene Expression Regulation , Histones/metabolism , Humans , Immunity, Innate/genetics , Influenza A Virus, H5N1 Subtype/drug effects , Influenza A Virus, H5N1 Subtype/immunology , Interferon Type I/metabolism , Male , Myeloid Cells/metabolism , Polysorbates/pharmacology , Squalene/pharmacology , Toll-Like Receptors/metabolism , Transcription Factor AP-1/metabolism , Transcriptome/genetics , Young Adult , alpha-Tocopherol/pharmacologyABSTRACT
Emerging evidence indicates a central role for the microbiome in immunity. However, causal evidence in humans is sparse. Here, we administered broad-spectrum antibiotics to healthy adults prior and subsequent to seasonal influenza vaccination. Despite a 10,000-fold reduction in gut bacterial load and long-lasting diminution in bacterial diversity, antibody responses were not significantly affected. However, in a second trial of subjects with low pre-existing antibody titers, there was significant impairment in H1N1-specific neutralization and binding IgG1 and IgA responses. In addition, in both studies antibiotics treatment resulted in (1) enhanced inflammatory signatures (including AP-1/NR4A expression), observed previously in the elderly, and increased dendritic cell activation; (2) divergent metabolic trajectories, with a 1,000-fold reduction in serum secondary bile acids, which was highly correlated with AP-1/NR4A signaling and inflammasome activation. Multi-omics integration revealed significant associations between bacterial species and metabolic phenotypes, highlighting a key role for the microbiome in modulating human immunity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antibodies, Viral/immunology , Gastrointestinal Microbiome/physiology , Immunity/drug effects , Influenza Vaccines/immunology , Influenza, Human/immunology , Adolescent , Adult , Antibody Formation , Female , Gastrointestinal Microbiome/drug effects , Healthy Volunteers , Humans , Immunogenicity, Vaccine/immunology , Influenza A Virus, H1N1 Subtype/immunology , Male , Young AdultABSTRACT
Herpes zoster (shingles) causes significant morbidity in immune compromised hosts and older adults. Whereas a vaccine is available for prevention of shingles, its efficacy declines with age. To help to understand the mechanisms driving vaccinal responses, we constructed a multiscale, multifactorial response network (MMRN) of immunity in healthy young and older adults immunized with the live attenuated shingles vaccine Zostavax. Vaccination induces robust antigen-specific antibody, plasmablasts, and CD4+ T cells yet limited CD8+ T cell and antiviral responses. The MMRN reveals striking associations between orthogonal datasets, such as transcriptomic and metabolomics signatures, cell populations, and cytokine levels, and identifies immune and metabolic correlates of vaccine immunity. Networks associated with inositol phosphate, glycerophospholipids, and sterol metabolism are tightly coupled with immunity. Critically, the sterol regulatory binding protein 1 and its targets are key integrators of antibody and T follicular cell responses. Our approach is broadly applicable to study human immunity and can help to identify predictors of efficacy as well as mechanisms controlling immunity to vaccination.
Subject(s)
Herpes Zoster Vaccine/immunology , Adaptive Immunity , Adult , Aged , Aging , Antibody Formation , CD4-Positive T-Lymphocytes/immunology , Female , Flow Cytometry , Gene Expression Profiling , Gene Regulatory Networks , Humans , Inositol Phosphates/immunology , Longitudinal Studies , Male , Metabolomics , Middle Aged , Sex Characteristics , Sterols/metabolism , Viral LoadABSTRACT
Many vaccines induce protective immunity via antibodies. Systems biology approaches have been used to determine signatures that can be used to predict vaccine-induced immunity in humans, but whether there is a 'universal signature' that can be used to predict antibody responses to any vaccine is unknown. Here we did systems analyses of immune responses to the polysaccharide and conjugate vaccines against meningococcus in healthy adults, in the broader context of published studies of vaccines against yellow fever virus and influenza virus. To achieve this, we did a large-scale network integration of publicly available human blood transcriptomes and systems-scale databases in specific biological contexts and deduced a set of transcription modules in blood. Those modules revealed distinct transcriptional signatures of antibody responses to different classes of vaccines, which provided key insights into primary viral, protein recall and anti-polysaccharide responses. Our results elucidate the early transcriptional programs that orchestrate vaccine immunity in humans and demonstrate the power of integrative network modeling.
Subject(s)
Meningococcal Infections/prevention & control , Meningococcal Vaccines/immunology , Neisseria meningitidis/immunology , Systems Biology/methods , Adolescent , Adult , Antibody Formation/genetics , Computer Simulation , Female , Humans , Immunity, Active , Immunoglobulins/blood , Influenza Vaccines/immunology , Male , Meningococcal Infections/immunology , Middle Aged , Transcriptome , Vaccines, Conjugate/immunology , Yellow Fever Vaccine/immunology , Young AdultABSTRACT
The clinical trajectory of COVID-19 may be influenced by previous responses to heterologous viruses. We examined the relationship of Abs against different viruses to clinical trajectory groups from the National Institutes of Health IMPACC (Immunophenotyping Assessment in a COVID-19 Cohort) study of hospitalized COVID-19 patients. Whereas initial Ab titers to SARS-CoV-2 tended to be higher with increasing severity (excluding fatal disease), those to seasonal coronaviruses trended in the opposite direction. Initial Ab titers to influenza and parainfluenza viruses also tended to be lower with increasing severity. However, no significant relationship was observed for Abs to other viruses, including measles, CMV, EBV, and respiratory syncytial virus. We hypothesize that some individuals may produce lower or less durable Ab responses to respiratory viruses generally (reflected in lower baseline titers in our study), and that this may carry over into poorer outcomes for COVID-19 (despite high initial SARS-CoV-2 titers). We further looked at longitudinal changes in Ab responses to heterologous viruses, but found little change during the course of acute COVID-19 infection. We saw significant trends with age for Ab levels to many of these viruses, but no difference in longitudinal SARS-CoV-2 titers for those with high versus low seasonal coronavirus titers. We detected no difference in longitudinal SARS-CoV-2 titers for CMV seropositive versus seronegative patients, although there was an overrepresentation of CMV seropositives among the IMPACC cohort, compared with expected frequencies in the United States population. Our results both reinforce findings from other studies and suggest (to our knowledge) new relationships between the response to SARS-CoV-2 and Abs to heterologous viruses.
Subject(s)
COVID-19 , Cytomegalovirus Infections , Influenza, Human , Respiratory Syncytial Virus, Human , Humans , SARS-CoV-2ABSTRACT
INTRODUCTION: Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality. METHODS: We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine: placebo) trial of 30 µg HEV-239 (Hecolin®, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM). RESULTS: Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at one month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked one month following the second dose (Geometric Mean Concentration (GMC) 6.16; 95% CI 4.40-8.63), was boosted with the third dose (GMC 11.50; 95% CI 7.90-16.75) and persisted through 6 months. CONCLUSIONS: HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults. CLINICAL TRIALS REGISTRATION: NCT03827395. Safety Study of Hepatitis E Vaccine (HEV239) - Full Text View - ClinicalTrials.gov.
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BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illness (ARI) in older adults. Optimizing diagnosis could improve understanding of RSV burden. METHODS: We enrolled adults ≥50 years of age hospitalized with ARI and adults of any age hospitalized with congestive heart failure or chronic obstructive pulmonary disease exacerbations at two hospitals during two respiratory seasons (2018-2020). We collected nasopharyngeal (NP) and oropharyngeal (OP) swabs (n=1558), acute and convalescent sera (n=568), and expectorated sputum (n=153) from participants, and recorded standard-of-care (SOC) NP results (n=805). We measured RSV antibodies by two immunoassays and performed BioFire testing on respiratory specimens. RESULTS: Of 1,558 eligible participants, 92 (5.9%) tested positive for RSV by any diagnostic method. Combined NP/OP PCR yielded 58 positives, while separate NP and OP testing identified 11 additional positives (18.9% increase). Compared to Study NP/OP PCR alone, the addition of paired serology increased RSV detection by 42.9% (28 vs 40) among those with both specimen types, while the addition of SOC swab RT-PCR results increased RSV detection by 25.9% (47 vs 59). CONCLUSIONS: The addition of paired serology testing, SOC swab results, and separate testing of NP and OP swabs improved RSV diagnostic yield in hospitalized adults.
ABSTRACT
Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802.
ABSTRACT
INTRODUCTION: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines. METHODS: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results. RESULTS: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections. CONCLUSIONS: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease.
ABSTRACT
BACKGROUND: Data are limited on influenza vaccine effectiveness (VE) in the prevention of influenza-related hospitalizations in older adults and those with underlying high-risk comorbidities. METHODS: We conducted a prospective, test-negative, case-control study at 2 US hospitals from October 2018-March 2020 among adults aged ≥50 years hospitalized with acute respiratory illnesses (ARIs) and adults ≥18 years admitted with congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) exacerbations. Adults were eligible if they resided in 1 of 8 counties in metropolitan Atlanta, Georgia. Nasopharyngeal and oropharyngeal swabs were tested using BioFire FilmArray (bioMérieux, Inc.) respiratory panel, and standard-of-care molecular results were included when available. Influenza vaccination history was determined from the Georgia vaccine registry and medical records. We used multivariable logistic regression to control for potential confounders and to determine 95% confidence intervals (CIs). RESULTS: Among 3090 eligible adults, 1562 (50.6%) were enrolled. Of the 1515 with influenza vaccination history available, 701 (46.2%) had received vaccination during that season. Influenza was identified in 37 (5.3%) vaccinated versus 78 (9.6%) unvaccinated participants. After adjustment for age, race/ethnicity, immunosuppression, month, and season, pooled VE for any influenza-related hospitalization in the eligible study population was 63.1% (95% CI, 43.8-75.8%). Adjusted VE against influenza-related hospitalization for ARI in adults ≥50 years was 55.9% (29.9-72.3%) and adjusted VE against influenza-related CHF/COPD exacerbation in adults ≥18 years was 80.3% (36.3-93.9%). CONCLUSIONS: Influenza vaccination was effective in preventing influenza-related hospitalizations in adults aged ≥50 years and those with CHF/COPD exacerbations during the 2018-2020 seasons.
Subject(s)
Heart Failure , Influenza Vaccines , Influenza, Human , Pulmonary Disease, Chronic Obstructive , Humans , Aged , Influenza, Human/epidemiology , Influenza, Human/prevention & control , Case-Control Studies , Prospective Studies , Pandemics , Vaccine Efficacy , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/epidemiology , Heart Failure/epidemiology , Vaccination , Hospitalization , SeasonsABSTRACT
INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15â µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75â µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.
Subject(s)
Antibodies, Viral , Immunization, Secondary , Influenza A Virus, H7N9 Subtype , Influenza Vaccines , Influenza, Human , Vaccines, Inactivated , Humans , Influenza Vaccines/immunology , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Adult , Male , Female , Middle Aged , Influenza A Virus, H7N9 Subtype/immunology , Vaccines, Inactivated/immunology , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects , Antibodies, Viral/blood , Influenza, Human/prevention & control , Influenza, Human/immunology , Young Adult , Immunization Schedule , Hemagglutination Inhibition Tests , United States , Immunogenicity, Vaccine , Antibodies, Neutralizing/blood , Polysorbates/administration & dosage , Polysorbates/adverse effects , alpha-Tocopherol/administration & dosage , alpha-Tocopherol/adverse effects , Squalene/administration & dosage , Squalene/adverse effects , Squalene/immunology , Healthy Volunteers , Drug Combinations , Adjuvants, Vaccine/administration & dosage , Vaccination/methods , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effectsABSTRACT
BACKGROUND: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. RESULTS: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.
Subject(s)
COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Vaccine Efficacy , Humans , COVID-19/prevention & control , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , Male , Female , SARS-CoV-2/immunology , Middle Aged , Adult , Immunocompromised Host , Aged , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , Adolescent , Adult , Aged , COVID-19/diagnosis , COVID-19/immunology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Incidence , Male , Middle Aged , Patient Acuity , Single-Blind Method , Spike Glycoprotein, Coronavirus , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , COVID-19 Drug Treatment , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Azetidines/adverse effects , COVID-19/mortality , COVID-19/therapy , Double-Blind Method , Drug Therapy, Combination , Female , Hospital Mortality , Hospitalization , Humans , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Male , Middle Aged , Oxygen Inhalation Therapy , Purines/adverse effects , Pyrazoles/adverse effects , Respiration, Artificial , Sulfonamides/adverse effects , Treatment OutcomeABSTRACT
Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.
Subject(s)
Antibodies, Viral/genetics , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Transcriptome/immunology , Adult , Aged , Antibodies, Viral/blood , Female , Flow Cytometry , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Seasons , Systems AnalysisABSTRACT
Chronic kidney disease affects more than 800 million people worldwide and often progresses to end-stage renal disease, which requires maintenance dialysis. Patients receiving dialysis are at higher risk for severe respiratory infections, including SARS-CoV-2 (the causative agent of COVID-19). In addition, many patients who receive dialysis also receive immunosuppressive treatments for conditions such as systemic vasculitis, systemic lupus erythematosus, or malignancies. Many studies have shown that while mRNA COVID-19 vaccines induce some level of immune response in patients receiving dialysis, the magnitude of response is often lower than that of healthy individuals, and responses rapidly wane. Importantly, the risk of COVID-19-related hospitalization and mortality for patients receiving dialysis is 4- to 8-fold higher compared with the general population. In this article, we summarize recent immunogenicity and real-world outcomes of COVID-19 mRNA vaccination among patients receiving dialysis, with a focus on the 3-dose extended primary series and additional (fourth) doses.
Subject(s)
COVID-19 Vaccines , COVID-19 , Humans , COVID-19/prevention & control , SARS-CoV-2 , Renal Replacement Therapy , Vaccination , Immunity , RNA, Messenger , Antibodies, ViralABSTRACT
BACKGROUND: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study. METHODS: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding. RESULTS: Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers ≥40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events. CONCLUSIONS: We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. Clinical Trials Registration. NCT04044352.
Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza Vaccines , Influenza, Human , Humans , Adult , Influenza, Human/prevention & control , Antibodies, Viral , Research Design , Hemagglutination Inhibition TestsABSTRACT
BACKGROUND: A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development. METHODS: In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture. RESULTS: Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males. CONCLUSIONS: The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process. CLINICAL TRIALS REGISTRATION: NCT01868464 (ClinicalTrials.gov).
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We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.
Subject(s)
2019-nCoV Vaccine mRNA-1273 , Adult , Humans , Vaccines, Combined , Clinical Protocols , RNA, Messenger/geneticsABSTRACT
Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.