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Volume 230, Issue 3, 15 September 2024
Editorial Commentary
An Anti-inflammatory Approach to Drug Repurposing for Clostridioides difficile Infection
Viewpoint
Hepatitis B Surface Antigen Loss: What Does Integration Have to Do With a Functional Hepatitis B Virus Cure?
ID Translational Science Update
An Update on Highly Pathogenic Avian Influenza A(H5N1) Virus, Clade 2.3.4.4b
Clinical Commentary
Personal Protective Equipment Guidance for Highly Pathogenic Avian Influenza H5N1 Should Be Adapted to Meet the Needs of Dairy Farm Workers
Major Articles and Brief Reports
Bacterial Disease Pathogenesis
Loratadine as an Anti-inflammatory Agent Against Clostridium difficile Toxin B
Neutrophil-Associated Proteins as Novel Biomarkers Elevated in Cerebrospinal Fluid of Patients With Neurosyphilis
Neutrophil-associated proteins (CXCL1, CXCL8, G-CSF, LCN2, MMP8, and MMP9) are significantly elevated in neurosyphilis. These elevated proteins could be associated with central nervous system damage of neurosyphilis. CSF CXCL8, MMP9, and LCN2 are promising biomarkers for diagnosing neurosyphilis.
Interferon-γ Responses to Chlamydia trachomatis Vaccine Candidate Proteins in Women With Different Chlamydia Outcomes
We investigated IFN-γ responses to Chlamydia trachomatis vaccine candidate proteins MOMP and Pmps E, F, G, and H using PBMCs from women with different chlamydia outcomes and found responses were heterogenous and primarily directed against MOMP and PmpE.
Heptavalent O-Antigen Bioconjugate Vaccine Exhibiting Differential Functional Antibody Responses Against Diverse Klebsiella pneumoniae Isolates
Adjunctive Pascolizumab in Rifampicin-Susceptible Pulmonary Tuberculosis: Proof-of-Concept, Partially-Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Trial
We evaluated pascolizumab (anti–IL-4 monoclonal antibody) as adjunctive tuberculosis treatment. There were no pascolizumab-related serious or grade 4 adverse events. The rate of increase in time to positivity on serial sputum samples was consistent with faster clearance with pascolizumab.
Large Clusters of Invasive emm49 Group A Streptococcus Identified Within Arizona Health Care Facilities Through Statewide Genomic Surveillance System, 2019–2021
Implementation of a statewide genomic surveillance system for invasive group A Streptococcus led to the early identification and investigation of a rapidly growing and prolonged outbreak of emm49 linked to several health care settings across Arizona.
A Machine Learning–Based Risk Score for Prediction of Infective Endocarditis Among Patients With Staphylococcus aureus Bacteremia—The SABIER Score
We developed a random forest risk score based on an 11-year territory-wide electronic health record to stratify the risk of infective endocarditis in patients with Staphylococcus aureus bacteremia at the time of blood culture positivity.
Eradication of Staphylococcus aureus in Implant-Associated Osteomyelitis by an Injectable In Situ-Forming Depot Antibiotics Delivery System
Formulations of antimicrobials in a new drug delivery system, were optimized in infected rodent models and evaluated in a porcine osteomyelitis model. Here, Staphylococcus aureus was eliminated from bones and implants in 9/12 and was fully eradicated in 5/12 pigs.
COVID-2019 Disease Pathogenesis
SARS-CoV-2 RNA and Nucleocapsid Antigen Are Blood Biomarkers Associated With Severe Disease Outcomes That Improve in Response to Remdesivir
In a randomized trial that compared remdesivir vs placebo in patients hospitalized with COVID-19, plasma viral RNA and serum nucleocapsid antigen levels were associated with worse outcomes. Decreases in these blood biomarkers correlated with clinical benefit from antiviral therapy.
Longitudinal Analysis of Nursing Home Residents’ T-Cell Responses After SARS-CoV-2 mRNA Vaccinations Shows Influence of Biological Sex and Infection History
T-cells responses in nursing home residents (NHR) and health care workers (HCW) after SARS-CoV-2 mRNA vaccination show that both groups have vaccine-induced responses, but prior infection and female sex contribute to higher responses in NHR but not HCW.
Informing the Need for a SARS-CoV-2 Booster Based on the Immune Responses Among Young Healthy Adults to Variants Circulating in Late 2023
Significant reduction in spike-specific binding and neutralizing antibodies was observed against SARS-CoV-2 variants circulating in late 2023 in young healthy adults, particularly those with a remote COVID-19 exposure, suggesting potential selective benefits of the updated XBB.1.5-based booster in this population.
Compartmentalized SARS-CoV-2 Replication in the Upper vs Lower Respiratory Tract After Intranasal Inoculation or Aerosol Exposure
Aerosol-inoculated rhesus macaques showed widespread SARS-CoV-2 replication in the respiratory tract, contrasting with limited replication in the upper tract via intranasal inoculation.
Antibody Titers and the Risk of Infection During the SARS-CoV-2 Omicron Phase in Bizen City, Japan
Higher anti-RBD IgG antibody titers were associated with a lower risk of SARS-CoV-2 infection. The risk decreased as a participant's antibody titer increased and the slope became flat around antibody titers of 10 000 AU/mL using natural cubic spline curves.
The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients
HIV/AIDs
Clonal Hematopoiesis in Patients With Human Immunodeficiency Virus and Cancer
People with HIV and cancer are 4 times more likely to have clonal hematopoiesis than similar people with cancer and without HIV. Decreased overall survival for patients with cancer and clonal hematopoiesis is more pronounced in people with HIV.
Drug Concentrations in Hair and Dried Blood Spots as Preexposure Prophylaxis Adherence Metrics During Pregnancy and Postpartum
A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention
In a phase 1 study, a fast-dissolving insert containing tenofovir alafenamide and elvitegravir administered rectally was shown to be safe in healthy volunteers. High rectal tissue concentrations of tenofovir diphosphate and elvitegravir, and ex vivo tissue anti-HIV activity were demonstrated.
Viral Disease Pathogenesis
Unraveling the Immune Signature of Herpes Zoster: Insights Into the Pathophysiology and Human Leukocyte Antigen Risk Profile
Using gene expression and association studies, our research uncovered the major histocompatibility complex locus as a major risk factor for the development of herpes zoster. Additionally, a clear type I interferon and adaptive immune signature were identified in individuals with herpes zoster.
Metabolomic Signatures Differentiate Immune Responses in Avian Influenza Vaccine Recipients
Following AS03-adjuvanted influenza A/H5N1 vaccine, enrichment of tryptophan, tyrosine, and nicotinate metabolism pathways was associated with serologic response. More specifically, increased urine abundance of benzoate-metabolism–related 4-vinylphenol sulfate on day 1 postvaccination was highly associated with serologic response.
Association of Oral Microbiome With Oral Human Papillomavirus Infection: A Population Study of the National Health and Nutrition Examination Survey, 2009–2012
Oral microbiome α-diversity (within-sample richness and phylogenetic diversity) and β-diversity (Bray-Curtis dissimilarity and unweighted UniFrac distance) are associated with high-risk oral HPV infection, and the associations are driven by males.
Mucosal Immunity to Poliovirus in Children 0–15 Years of Age: A Community-Based Study in Karachi, Pakistan in 2019
One-seventh (14%) of participants excreted poliovirus after bivalent oral poliovirus vaccine challenge. Most had prior humoral immunity to poliovirus (PV), but some lacked mucosal immunity. This poses PV transmission risk to communities if replication-competent PV, whether wild-type or vaccine-derived, were to be introduced.
Identification of CCL20 as a Prognostic Predictor for Severe Fever With Thrombocytopenia Syndrome Based on Plasma Proteomics
We used the Olink Proteomics assay to investigate the plasma prognostic predictors of severe fever with thrombocytopenia syndrome and identified 110 differentially expressed proteins in nonsurvivors, mainly enriched in cell chemoattraction–related pathways. C-C motif chemokine 20 emerged as a notable predictor of death in patients with severe fever with thrombocytopenia syndrome.
Correlates of Rotavirus Vaccine Shedding and Seroconversion in a US Cohort of Healthy Infants
In this US-based birth cohort, maternal IgG was negatively associated with rotavirus vaccine immune response. Immune response was least common among infants with a single-nucleotide polymorphism inactivating FUT2 antigen secretion (“nonsecretors”) whose mothers were also nonsecretors, versus all other combinations.
Fungi
Impact of Micafungin on Candida auris β-glucan Masking and Neutrophil Interactions
The drug-resistant pathogen Candida auris causes invasive disease with limited treatment options. While echinocandins can unmask immunostimulatory β-glucan and augment immunity for Candida albicans, we found only minimal unmasking for C. auris isolates, revealing altered regulation of this pathway.
Candida albicans N-Linked Mannans Potentiate the Induction of Trained Immunity via Dectin-2
This study investigates the role of mannosylation of Candida albicans cell wall in innate immune responses. Recognition of N-linked mannans, particularly the α1,6-mannose backbone, by dectin 2 is shown to be crucial for cytokine production and induction of trained immunity.
Correspondence
Comment on: A Call to Action: Urgently Strengthening the Future Physician-Scientist Workforce in Infectious Diseases
Reply to Barajas-Ochoa: The Imperative to Integrate International Medical Graduates into the Infectious Diseases Physician-Scientist Pathway: Expanding Opportunities and Overcoming Barriers
Online-only Articles
Epilogue Reflections
In Memoriam: W. Michael Scheld, MD
ID Translational Science Update
Antibiofilm Agents for the Treatment and Prevention of Bacterial Vaginosis: A Systematic Narrative Review
The treatment of bacterial vaginosis (BV) is complicated by the antibiotics’ inability to penetrate BV biofilms. This review informs clinicians about a variety of investigated BV biofilm removal treatments and their efficacy, as well as particularly promising recent treatment approaches with enzymes and probiotics.
Major Articles and Brief Reports
Bacterial Disease Pathogenesis
IL-17 and IFN-γ–producing Respiratory Tissue-Resident Memory CD4 T Cells Persist for Decades in Adults Immunized as Children With Whole-Cell Pertussis Vaccines
Most studies on T-cell responses to mucosal pathogens focus on the blood. Here we demonstrate tissue-resident memory T cells persist in the tonsil and nasal tissue of humans for decades after immunization with whole-cell pertussis vaccines.
Uncovering the Bronchoalveolar Single-Cell Landscape of Patients With Pulmonary Tuberculosis With Human Immunodeficiency Virus Type 1 Coinfection
We utilized single-cell RNA sequencing technology to provide a detailed analysis of immune cells in the lungs of patients with tuberculosis (TB) or with HIV–TB coinfection. Our findings revealed notable variations in immune response between these 2 disease types.
Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis
We found that clonal strains of Pseudomonas persist after elexacaftor-tezacaftor-ivacaftor treatment with the same “chronic” phenotypes that are just as clinically challenging in people with cystic fibrosis. We further identified commonly mutated bacterial genes that may drive future adaptation to the CFTR (cystic fibrosis transmembrane conductance regulator) modulated lung.
Uropathogenic Escherichia coli Subverts Host Autophagic Defenses by Stalling Preautophagosomal Structures to Escape Lysosome Exocytosis
This study uncovers a critical role of PldA through reducing intracellular PI3P levels to inhibit preautophagosomal structure maturation and autophagic flux, favoring UPEC escape from host lysosome exocytosis, thereby contributing to acute UTI.
Incidence of Invasive and Noninvasive Pneumococcal Pneumonia Hospitalizations in People Aged ≥50 Years: Assessing Variability Across Denmark and Spain
The burden of pneumococcal pneumonia (PP) requiring hospitalization among older adults in Europe remains considerable. Estimates of invasive and noninvasive PP incidence among European countries vary between 2 and 6 times. Country-specific clinical practice hampers comparability of pneumonia in Europe.
A Comparative Phenotypic and Genomic Analysis of Methicillin-Resistant Staphylococcus aureus ST45 Isolates From Cellulitis and Osteomyelitis in Taiwan
This study examined MRSA ST45 isolates collected from cellulitis (superficial infection) and osteomyelitis (invasive infection) in a Taiwan hospital, and highlighted the phenotypic and genomic differences between isolates causing cellulitis versus osteomyelitis.
COVID-2019 Disease Pathogenesis
A Novel Anti-nucleocapsid Antibody Avidity Method for Identifying SARS-CoV-2 Reinfections
Measuring the high-avidity anti-nucleocapsid (N) IgG detected SARS-CoV-2 reinfections after de novo infection with improved specificity compared to anti-N IgG levels. This method allows retroactive study of the epidemiology and health consequences of asymptomatic or unreported reinfections.
Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Following Prior Infection or Vaccination
In a cohort study of 4496 community-dwelling adults during the initial year of Omicron, prior infection and vaccination both offered protection against new SARS-CoV-2 infection. Importantly, remote prior infection was less protective than remote vaccination for individuals aged ≥60 years.
Safety and Immunogenicity of the mRNA-1273 Coronavirus Disease 2019 Vaccine in Solid Organ Transplant Recipients
Messenger RNA–1273 (100 μg) administered as a 3-dose primary series and an additional dose was well tolerated among solid organ transplant recipients. Antibody responses were improved after dose 3 and the additional dose, supporting the recommended doses for this immunocompromised population.
High Frequency of Prior Severe Acute Respiratory Syndrome Coronavirus 2 Infection by Sensitive Nucleocapsid Assays
Longitudinal Evaluation of Severe Acute Respiratory Syndrome Coronavirus 2 T-Cell Immunity Over 2 Years Following Vaccination and Infection
Cellular and serological responses was evaluated in a cohort of 639 SARS-CoV-2–vaccinated participants. There was a significant increase in SARS-CoV-2 spike–specific T-cell responses following each booster dose. Furthermore, SARS-CoV-2 infection boosts both the cellular and humoral immune response.
HIV/AIDs
Distinct Inflammatory Phenotypes Are Associated With Subclinical and Clinical Cardiovascular Disease in People With Human Immunodeficiency Virus
Population Effectiveness of Dolutegravir Implementation in Uganda: A Prospective Observational Cohort Study (DISCO), 48-Week Results
Among people with HIV in Uganda who transitioned to TLD, we observed high rates of viral suppression, high tolerability, and no emergent drug resistance, all of which support use of TLD as the preferred first-line regimen in the region.
Genetic Diversity From Proviral DNA as a Proxy for Time Since HIV-1 Infection
Knowing the time since infection with HIV is important for clinical care and research, yet it is often unknown. We show here that this time can be estimated from the diversity observed in proviral DNA.
Viral Disease Pathogenesis
Safety, Tolerability, and Immunogenicity of an mRNA-Based Respiratory Syncytial Virus Vaccine in Healthy Young Adults in a Phase 1 Clinical Trial
Respiratory syncytial virus presents a global health concern. We assessed the safety and immunogenicity of an mRNA-based vaccine, mRNA-1345, in healthy adults aged 18 to 49 years. mRNA-1345 vaccine was well tolerated and immunogenic in younger adults.
Safety and Immunogenicity of an mRNA-Based RSV Vaccine Including a 12-Month Booster in a Phase 1 Clinical Trial in Healthy Older Adults
Older adults and those with comorbidities are at increased risk of severe RSV. We assessed the safety and immunogenicity of mRNA-1345, an RSV vaccine, in adults aged 65 to 79 years. mRNA-1345 was well tolerated and immunogenic following a single injection and 12-month booster.
Effect of Pneumococcal Conjugate Vaccines on Viral Respiratory Infections: A Systematic Literature Review
Emerging evidence indicates that pneumococcal conjugate vaccines (PCVs) not only reduce pneumococcal disease burden but also might indirectly reduce viral respiratory tract infections by affecting pneumococcal–viral interactions. We summarized available evidence on PCV protection against virus-related respiratory tract infections in children and adults.
Safety and Immunogenicity of a Messenger RNA–Based Cytomegalovirus Vaccine in Healthy Adults: Results From a Phase 1 Randomized Clinical Trial
The mRNA-based cytomegalovirus (CMV) vaccine, mRNA-1647, was evaluated at the 30-, 90-, 180-, and 300-μg dose levels in a phase 1 trial in CMV-seronegative and CMV-seropositive adults. mRNA-1647 had an acceptable safety profile and elicited humoral and cellular immune responses.
Growing Awareness: Limited Testing and Screening Bias for Hepatitis Delta Virus in Utah 2000–2021
This 22-year study at University of Utah UHealth reveals only 22.2% of HBV patients were tested for HDV, with an 8.3% HDV positivity rate. Findings underscore the need for enhanced HDV testing to increase the early detection of HDV.
Enrichment Reveals Extensive Integration of Hepatitis B Virus DNA in Hepatitis Delta Virus-Infected Patients
Explant tissue deep RNA sequencing showed that HBV DNA integrates extensively, but great variation in S-RNA levels suggests that a small part of the integrations determines serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis.
Relationship Between Hepatitis C Infection and Treatment Status and Coronavirus Disease 2019–Related Hospitalizations in Georgia
This Georgian population-based registry study indicates that hepatitis C virus (HCV)–positive individuals treated with direct-acting antivirals may have reduced odds of COVID-19–related hospitalization compared with those who remained untreated for HCV or tested HCV negative.
Monitoring Progress Towards the Elimination of Hepatitis C as a Public Health Threat in Norway: A Modelling Study Among People Who Inject Drugs and Immigrants
We estimate that Norway, a setting with a concentrated epidemic, high coverage of harm reduction services, and no treatment restrictions, has achieved the global incidence target for the elimination of hepatitis C among people who inject drugs.
DOCK2 Deficiency Causes Defects in Antiviral T-Cell Responses and Impaired Control of Herpes Simplex Virus Infection
DOCK2 deficiency was explored in a model of herpes simplex virus infection and immunity, finding a critical role for this protein in antiviral CD8+ T-cell priming and initial expansion.
Risk of Cardiovascular Events After Influenza: A Population-Based Self-Controlled Case Series Study, Spain, 2011–2018
The risk of atherothrombotic events more than doubled during the 14 days following milder influenza cases in individuals with fewer risk factors. After severe cases in more vulnerable patients, it more than quadrupled, remaining elevated by 2-fold for 2 months.
Exploring JC Polyomavirus Sequences and Human Gene Expression in Brain Tissue of Patients With Progressive Multifocal Leukoencephalopathy
Brain tissue of patients with progressive multifocal leukoencephalopathy (PML) harbors rearranged variants of the causative agent JC polyomavirus. Strong regulation of genes associated with neuroinflammation, blood-brain barrier permeability, and neurodegenerative diseases provides new prospects for understanding PML pathogenesis.
Malaria
Functional and Immunologic Mapping of Domains of the Reticulocyte-Binding Protein Plasmodium vivax PvRBP2a
Here, we identify 2 clusters of epitopes mediating the functional interaction between the Plasmodium vivax invasion ligand PvRBP2a and its host receptor CD98. Our data reveal important epitopes for development of a P vivax blood-stage vaccine.
From Genome-wide Association Studies to Functional Variants: ARL14 Cis-regulatory Variants Are Associated With Severe Malaria
We identified an ARL14 cis-regulatory region containing functional single-nucleotide polymorphisms (SNPs) associated with severe malaria and provided evidence of allele-specific promoter activity. Hence, these SNPs could be involved in the development of severe malaria by regulating ARL14 expression and consequently T-lymphocyte activation.
Declining Antibody Affinity Over Time After Human Vaccination With a Plasmodium falciparum Merozoite Vaccine Candidate
Maintaining high-affinity antibodies after vaccination may be important for long-lasting immunity to malaria, but knowledge is lacking. In a phase 1 malaria vaccine trial, affinity of vaccine antibodies declined substantially over 12 months, suggesting poor maintenance of high-affinity antibodies.