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Volume 231, Issue 4, 15 April 2025
Editorial Commentary
Genomics Should Inform Appropriate Analysis of Taxonomy and Pathogenesis of Rickettsia
Special Collection on Vaccine Sciences
Maternal Immunization
Perspective
Economic Analyses for Disease Surveillance Planning and Advocacy
Public health disease surveillance can guide decisions related to the protection of populations. Economic analysis can be used to assess how disease surveillance can substitute for or complement other public health interventions and how to structure surveillance most efficiently.
ID Translational Science Update
Rationale and Ethical Assessment of an Oropharyngeal Gonorrhea Controlled Human Infection Model
Gonorrhea causes a high global burden of disease and significant long-term reproductive health sequelae, with antimicrobial resistance an increasing concern. Gonorrhea controlled human infection models may accelerate therapeutic and prevention strategies but require ethical assessment and risk mitigation.
Major Articles and Brief Reports
Bacterial Disease Pathogenesis
Rickettsia rickettsii subsp californica subsp nov, the Etiologic Agent of Pacific Coast Tick Fever
This work describes an integrative taxonomic approach to formally name the pathogen associated with Pacific Coast tick fever, identified previously with the ambiguous epithet of Rickettsia 364D. Herein, we propose the designation Rickettsia rickettsii subsp californica.
Engineered Mycobacteriophage TM4::GeNL Rapidly Determines Bedaquiline, Pretomanid, Linezolid, Rifampicin, and Clofazimine Sensitivity in Mycobacterium tuberculosis Clinical Isolates
We present a rapid, phage-based phenotypic drug susceptibility testing method for Mycobacterium tuberculosis. This method enables the determination of susceptibility to drugs in BPaL regimen within 48 hours, making it potentially valuable for implementation in low- and middle-income countries.
Increased Proportions of Invasive Pneumococcal Disease Cases Among Adults Experiencing Homelessness Sets the Stage for New Serotype 4 Capsular-Switch Recombinants
IPD continued to disproportionally occur in AEH during COVID-19/post–COVID-19 years. Increased and expanded serotype 4 IPD among AEH in western states coincided with the emergence of a genetically unique serotype 4 serotype-switch variant, which also disproportionally targeted AEH.
Epigenetic Changes in Cerebrospinal Fluid and Blood of People With Neurosyphilis
DNA methylation is sufficient to distinguish uncomplicated syphilis from neurosyphilis in cerebrospinal fluid (CSF) and blood, and most methylation changes in CSF persist after treatment. These signatures correlate with RNA expression in pathways involving insulin receptors, cytotoxic molecules, and B-cell activation.
First Report of a Fatal Septicemia Case Caused by Vibrio metoecus: A Comprehensive Functional and Genomic Study
We report the first case of death caused by septicemia due to V. metoecus and analyze the possible genetic basis of the septicemic potential in this newly emerging Vibrio species.
Genomic Epidemiology of Extrapulmonary Nontuberculous Mycobacteria Isolates at Emerging Infections Program Sites—United States, 2019–2020
Extrapulmonary nontuberculous mycobacteria isolates collected from 4 CDC Emerging Infections Program sites are diverse in species and sequence types. Here we demonstrate the utility of whole genome sequencing–based approaches for identification and characterization of nontuberculous mycobacteria for surveillance, epidemiologic studies, and outbreak investigations.
Serological Responses to Target Streptococcus pyogenes Vaccine Antigens in Patients With Proven Invasive β-Hemolytic Streptococcal Infections
Patients with invasive Streptococcus pyogenes infection demonstrate significant antibody responses to several non-M protein vaccine candidate antigens. Similar significant responses to the antigen C5a peptidase were also observed in both invasive Streptococcus agalactiae and Streptococcus dysgalactiae subspecies equisimilis infection.
COVID-2019 Disease Pathogenesis
Antibody Levels From High-Throughput Variant-Specific SARS-CoV-2 Anti-Spike Immunoglobulin G and Angiotensin-Converting Enzyme 2 Neutralization Assays Correlate With COVID-19 Infection Risk in a Large Population
High-throughput variant-specific antibody assays measure SARS-CoV-2 viral neutralization and protection. Antibody cut points can be derived to demarcate infection risk, though cut points differ by assay and variant, with higher sensitivity noted for circulating variant–aligned inhibition assays.
Distinguishing Multisystem Inflammatory Syndrome in Children From Typhus Using Artificial Intelligence: MIS-C Versus Endemic Typhus (AI-MET)
Using artificial intelligence, we developed a clinical decision support system that can rapidly distinguish between febrile patients suspected of having murine typhus or multisystem inflammatory syndrome in children (MIS-C).
Shortened SARS-CoV-2 Viral RNA Shedding in Saliva During Early Omicron Compared to Wild-Type Pandemic Phase
SARS-CoV-2 viral RNA shedding was studied in saliva to compare wild-type– and Omicron-infected participants. Preexisting immunity in participants seemed to shorten shedding duration and lower viral load peaks.
HIV/AIDs
Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People With Human Immunodeficiency Virus
In our study of people with HIV aged ≥45 years, elevated plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were associated with worse cognitive performance cross-sectionally. Longitudinally, higher NfL was associated with cognitive decline.
Patterns and Cofactors of Polyfunctional Mycobacteria-Specific T-Cell Response Restoration Following 6-Month Antiretroviral Treatment in Children With HIV
Despite increases in Th1 cytokine production, deficits in mycobacteria-specific CD4 T cells persisted 6 months after antiretroviral therapy in children with HIV. These findings may explain persistent TB risk during early antiretroviral therapy among children with HIV.
Combined Sequential Antiretroviral Therapy–Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss Are Cumulative in Mice Models
Using animal models, we show that fracture risk in postmenopausal women with HIV may be increased when bone loss from antiretroviral therapy is followed by menopause. Early screening and prophylaxis with anti-inflammatory drugs or probiotics may diminish fracture risk.
Healthy Aging and the Gut Microbiome in People With and Without HIV
Older age is associated with consistent changes in the gut microbiome in women and men with or without HIV, including higher diversity and uniqueness, and lower abundance of Prevotella and Faecalibacterium. Aging-related microbiota may contribute to aging-related declines in health.
Parasites
Rapid Antigen Detection Test for Diagnosis of Post–kala-azar Dermal Leishmaniasis: Application of CL Detect Rapid Test for Active Case Detection in the Endemic Area
This study assessed the CL Detect Rapid Test for diagnosing post–kala-azar dermal leishmaniasis. The test demonstrated 73.3% sensitivity and 100% specificity, making it a potential primary screening tool for active case detection of post–kala-azar dermal leishmaniasis in endemic regions.
CpG-Adjuvanted Virus-like Particle Vaccine Induces Protective Immunity Against Leishmania donovani Infection
Adjuvanting influenza virus-like particle vaccines expressing the Leishmania donovani promastigote surface antigen with CpG oligodeoxynucleotide augments vaccine-induced protection in mice.
An Expression Quantitative Trait Locus of Fc Gamma Receptor Genes Is Associated With Antimalarial IgG Responses and Infection Levels in Burkinabe Families
This study identifies the noncoding variant rs1771575 in the FCGR gene cluster as a key marker for IgG levels and malaria infection in children. It highlights the role of regulatory and coding variants in shaping immune responses to Plasmodium falciparum.
Impact of Late–Rainy Season Indoor Residual Spraying on Holoendemic Malaria Transmission: A Cohort Study in Northern Zambia
In a cohort study in northern Zambia, individuals in areas sprayed at the end of the rainy season had a reduced hazard of infection but no difference in odds of parasite prevalence when compared with individuals in unsprayed areas.
Viral Disease Pathogenesis
Nasal Mucosal Cytokines as Potential Biomarkers for Assessing Disease Severity and Class of Pathogen in Children With Community-Acquired Pneumonia
Nasal mucosal cytokines in children with community-acquired pneumonia can help classify patients according to disease severity and potentially by etiology. These findings are significant because they provide clinicians with a promising noninvasive tool for patient classification and tailored treatment.
Simultaneous Cocirculation of 2 Genotypes of Dengue Virus Serotype 3 Causing a Large Outbreak in Sri Lanka in 2023
The large dengue outbreak that occurred in 2023 in Sri Lanka was due to emergence of DENV-3, with cocirculation of 2 genotypes, which evaded detection by some molecular tests. This highlights the importance of continued surveillance activities, including genomic sequencing.
Immunogenicity, Safety, and Persistence Induced by Triple- and Standard-Strength 4-Dose Hepatitis B Vaccination Regimens in Patients Receiving Hemodialysis
Triple-strength 4-dose hepatitis B vaccination regimens could improve the immunogenicity and 2-year persistence compared with standard-strength 3-dose regimens in patients receiving hemodialysis. Anti-HBs levels dropped quickly during month 7 to 18 after the primary vaccination, while it dropped slowly thereafter.
Evaluation of Immunoglobulin A Enzyme Immunoassays to Detect Primary Respiratory Syncytial Virus Infection in Infants and Young Children
Our evaluation of a respiratory syncytial virus (RSV) F protein IgA enzyme immunoassay showed it has high sensitivity and specificity for detecting primary RSV infections in infants and young children with maternal IgG antibodies and can add value to RSV studies in these children.
Monkeypox Virus Infection Stimulates a More Robust and Durable Neutralizing Antibody Response Compared to Modified Vaccinia Virus Ankara Vaccination
Monkeypox virus (MPXV) infection elicits a more robust and durable neutralizing antibody response compared to vaccinia virus–based MVA-BN vaccination. These findings support further study of vaccine strategies to prevent breakthrough infections and maintain long-term immunity against MPXV.
Pathological Insights into Lassa Virus-Induced Vestibular Dysfunction in Mice: Histopathological Analysis of the Inner Ear Vestibular Apparatus
Lassa fever, caused by Lassa virus infection, frequently leads to hearing and balance dysfunction. The pathology observed in the inner ear vestibule of our Lassa fever model mice were hemorrhage, T-lymphocyte infiltration, and Lassa virus antigen in the neuronal structures.
Risk Stratification of Metabolic Risk Factors and Statin Use Associated With Liver and Nonliver Outcomes in Chronic Hepatitis B
Higher metabolic burden, particularly diabetes, was associated with greater risk for liver and nonliver complications in patients with chronic hepatitis B. Statin use was associated with reduced risk of liver outcomes among lower metabolic burden with ≤2 metabolic traits.
Detection of Live Attenuated Measles Virus in the Respiratory Tract Following Subcutaneous Measles-Mumps-Rubella Vaccination
This study shows that the live attenuated measles vaccine virus, which is delivered by injection, commonly travels to the respiratory tract in healthy infants and macaques, and that this may contribute to induction of robust mucosal immunity.
Online-Only Articles
Epilogue Reflections
Epilogue Reflection: Diane E. Griffin, MD, PhD
Major Articles and Brief Reports
Viral Disease Pathogenesis
Parvovirus B19 and Human Herpes Virus 6B and 7 Are Frequently Found DNA Viruses in the Human Thymus But Show No Definitive Link With Myasthenia Gravis
DNA viruses show no direct association with thymic pathology in myasthenia gravis, making them unlikely primary triggers of the disease. However, their persistence in both myasthenia gravis and histologically normal thymus may have potential implications for thymic function.
Efficacy of Laundry Practices in Eliminating Mpox Virus From Fabrics
In a trial of simulated manual clothes washing, sodium hypochlorite, liquid sanitizer, and 2 powdered laundry detergents in room temperature water, as well as 70°C water alone, completely inactivated mpox virus (> 99.9% inactivation) on both cotton and polyester fabrics.
Antibody-Based Antigen Delivery to Dendritic Cells as a Vaccination Strategy Against Ebola Virus Disease
Targeted delivery of the Ebola virus (EBOV) nucleoprotein or the model antigen ovalbumin (OVA) to dendritic cells expressing DEC-205 results in T-cell activation and protection against challenge with wild-type EBOV or a recombinant EBOV-OVA, respectively.
Socioeconomic Inequities in the Age-Specific Burden of Severe Respiratory Syncytial Virus in Canada, 2016–2019
In a cohort of Canadians ≥6 months of age, rates of respiratory syncytial virus (RSV)–related hospitalizations were higher among individuals of lower socioeconomic status (SES). Inequities in RSV disease burden and the relative importance of different SES indicators varied greatly by age.
Population-Based Age-Period-Cohort Analysis of Declining Human Papillomavirus Prevalence
We monitored the human papillomavirus (HPV) prevalence among the cervical screening population from 2014 to 2023. Among women eligible for school-based HPV vaccination, a 99% and 98% decline in HPV-16 and -18 infection, respectively, was observed. This indicates a strong overall protective effect.
Association Between Herpes Simplex Virus Type 2 and High-Risk Human Papillomavirus Infections: A Population Study of the National Health and Nutrition Examination Survey, 2009–2016
Herpes simplex virus type 2 infection raises the odds of high-risk human papillomavirus (HPV) infection, especially HPV-18 and HPV-58. This study underscores the importance of preventing herpes simplex virus and promoting early HPV vaccination among individuals at risk to reduce cervical cancer incidence.
Bacterial Disease Pathogenesis
FGF8 Protects Against Polymicrobial Sepsis by Enhancing the Host's Anti-infective Immunity
The underlying mechanism for high mortality associated with sepsis remains to be resolved. These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense, providing novel strategies for sepsis diagnosis and immunotherapy.
Genetically Diverse Mycobacterium tuberculosis Isolates Manipulate Inflammasome and Interleukin 1β Secretion Independently of Macrophage Metabolic Rewiring
The glycolytic pathway is required for maximum IL-1β production by macrophages infected with live distinct M. tuberculosis isolates, but mitochondria metabolic alterations are uncoupled from the inflammasome activation and IL-1β secretion by infected cells.
Comprehensive Assessment of Initial Adaptation of Extended-Spectrum β-Lactamase–Positive ST131 Escherichia coli to Carbapenem Exposure
High-risk ST131 Escherichia coli strains, particularly C2/H30Rx subclades, adapt to initial carbapenem exposure by insertion sequence–mediated extended-spectrum β-lactamase gene amplification. This gene amplification may precede stable mutations in porin genes, potentially leading to resistance with manageable fitness costs.
Molecular Epidemiology of Invasive Group B Streptococcus in South Africa, 2019–2020
This study analyzed 658 invasive Group B Streptococcus (GBS) isolates from South Africa between 2019 and 2020, revealing moderate erythromycin and clindamycin resistance. β-lactam antibiotics remain appropriate for treatment, and polysaccharide and protein-based vaccines are expected to provide good coverage.
Staphylococcus aureus Tetracycline Resistance and Co-resistance in a Doxycycline Postexposure Prophylaxis–Eligible Population
Among doxycycline postexposure prophylaxis (doxy-PEP)–eligible men, Staphylococcus aureus tetracycline nonsusceptibility is more prevalent than in the overall population and is associated with resistance to trimethoprim-sulfamethoxazole and clindamycin. Doxy-PEP may select for multidrug-resistant S aureus, underscoring the importance of surveillance.
Addition of Macrolide Antibiotics for Hospital Treatment of Community-Acquired Pneumonia
The study found no evidence that combining macrolides with β-lactam antibiotics improved clinical outcomes for patients hospitalized with community-acquired pneumonia, regardless of disease severity. Benefits of additional macrolides should be weighed against risks of adverse effects and resistance.
COVID-2019 Disease Pathogenesis
A Surrogate Enzyme-Linked Immunosorbent Assay to Select High-Titer Human Convalescent Plasma for Treating Immunocompromised Patients Infected With Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern
Factors Associated With the Transmission of the Delta Severe Acute Respiratory Syndrome Coronavirus 2 Variant in Households: The Israeli COVID-19 Family Study (ICoFS)
From a large household study in Israel, we developed a Bayesian model to assess how immunity, age, isolation, and contact influenced Delta variant transmission. Recent vaccination strongly reduced susceptibility, but this effect waned rapidly. Isolation and differential parental care significantly affected transmission.
Effectiveness of mRNA COVID-19 Vaccines and Hybrid Immunity in Preventing SARS-CoV-2 Infection and Symptomatic COVID-19 Among Adults in the United States
According to data from 3 prospective cohort studies where participants collected weekly nasal swabs, protection from COVID-19 vaccination against SARS-CoV-2 infection and symptomatic illness was highest among adults with prior infection and recent vaccination. Recent vaccination alone provided moderate protection.
Safety and Immunogenicity of SARS-CoV-2 Spike Receptor-Binding Domain and N-Terminal Domain mRNA Vaccine
The mRNA-1283 vaccine encoding the RBD and NTD of the SARS-CoV-2 spike protein was well tolerated and had improved immunogenicity compared with mRNA-1273, regardless of the vaccine valency (monovalent, bivalent) or the variant sequence tested (SARS-CoV-2 D614G, Beta, Omicron BA.1).
HIV/AIDs
HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines
A gp120 HIV vaccine produced by transiently transfected cells yielded similar immunogenicity and safety profiles to the equivalent protein produced by stable transfection.
Pre–Human Immunodeficiency Virus (HIV) α4β7hi CD4+ T Cells and HIV Risk Among Heterosexual Individuals in Africa
CD4+ T cells that express the gut homing integrin α4β7 are more readily infected by HIV, but as predictors of HIV acquisition, associations differ by cohort. Higher frequency of α4β7+ CD4+ T cells predicted faster disease progression in South Africans.
Associations Between the Gut Microbiome, Inflammation, and Cardiovascular Profiles in People With Human Immunodeficiency Virus
This study links gut microbiome alterations, particularly reduced short chain fatty acid–producing bacteria, to systemic inflammation, diet, and cardiovascular disease risk in people with and without HIV, suggesting that targeted dietary and gut microbiome interventions may mitigate cardiovascular risk in HIV infection.
Impact of Switching to Long-Acting Injectable Cabotegravir Plus Rilpivirine on Rectal HIV-1 RNA Shedding and Implications for Transmission Risk
Intermittent rectal HIV-1 RNA shedding is common with bimonthly intramuscular cabotegravir/rilpivirine, occurs independently of rectal rilpivirine levels, and is linked to higher pretreatment viral load.
Fungi
Candida albicans Recovered From Persistent Candidemia Exhibits Enhanced Virulence Traits
Candida albicans may enhance its pathogenic traits within the host during persistent candidemia, and these traits appear to be heritable across cell generations.
Use of Intravaginal Cooling to Provide Symptom Relief in Women With Vulvovaginal Candidiasis and Reduce Immunopathology in an Accompanying Mouse Model
Current therapies for vulvovaginal candidiasis often fail to prevent recurrences. This study demonstrates intravaginal cooling as an effective, nonpharmacologic approach to reduce symptoms by reverting Candida albicans hyphae to yeast, validated through pilot clinical trials and in proof-of-concept animal studies.