Complex intra-host SARS-CoV-2 evolution following monoclonal antibody pre-exposure prophylaxis 2309595

Complex intra-host SARS-CoV-2 evolution following monoclonal antibody pre-exposure prophylaxis

Intra-Host Evolution of SARS-CoV-2 During Persistent Infection of Pediatric COVID-19 Patients

Children typically experience milder SARS-CoV-2 infection than adults, yet a subset—especially those with immune compromise—develop persistent infection. This study examined clinical characteristics and intra-host viral evolution in pediatric patients with prolonged COVID-19, comparing immunocompetent and immunocompromised hosts. Residual nasopharyngeal specimens from patients <20 years old with ≥3 samples ≤90 days apart underwent qRT-PCR confirmation and whole-genome sequencing using tiled amplicon Illumina methods. Demographic, clinical, and immune-status data were extracted through chart review. Viral load trajectories and longitudinal genomic changes were analyzed. Sixteen patients met inclusion criteria: 5 immunocompetent and 11 immunocompromised children. Groups showed similar demographic distributions (mean ages 6 vs. 9.2 years; 60% vs. 64% male; 60% vs. 45% Hispanic). Vaccination was rare, with all immunocompetent and 82% of immunocompromised patients unvaccinated. COVID-19 treatment differed markedly: 1 immunocompetent (20%) versus 8 immunocompromised patients (73%) received therapies including monoclonal antibodies or remdesivir. Clinical severity varied, with immunocompetent children largely asymptomatic or managed as outpatients, whereas immunocompromised children more frequently required hospitalization (28%), ICU care (9%), or died (18%). Despite this, WHO severity scores were similar (2.4 vs. 2.2). Sequencing yielded 15 isolates from immunocompetent and 35 isolates from immunocompromised patients. Viral loads generally declined over time, though several immunocompromised children demonstrated prolonged high viral loads. Longitudinal sequencing identified intra-host viral diversification in both groups, including nonsynonymous Spike mutations and minority variants associated with immune escape. Some immunocompromised patients accumulated mutations at positions linked to therapeutic resistance. Pediatric persistent SARS-CoV-2 infection is associated with measurable intra-host viral evolution. Immunocompromised children demonstrated longer infection duration, more frequent treatment exposure, and extended viral shedding, creating conditions that may favor viral diversification. These findings highlight the need for continued genomic surveillance in vulnerable pediatric populations.

Twelve-month anti-SARS-CoV-2 antibody kinetics in COVID-19 patients from Bejaia, Algeria

The COVID-19 pandemic has highlighted the importance of understanding long-term humoral immunity after SARS-CoV-2 infection. This study evaluated the kinetics and persistence of anti-SARS-CoV-2 immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies in hospitalized patients who recovered and identified factors associated with antibody responses. A total of 96 patients hospitalized with real-time polymerase chain reaction-confirmed COVID-19 between June and September 2020 were included. Sequential serum samples were collected up to 365 days after symptom onset. Anti-SARS-CoV-2 IgM and IgG antibodies targeting spike (S) and nucleocapsid (N) proteins were evaluated on days 28, 90, 180, and 365 using chemiluminescent immunoassay (MAGLUMI). Clinical, epidemiological, and radiological data were analyzed. All convalescent patients developed detectable IgG antibodies, and 92.7% were IgG seropositive. Antibody titers and seropositivity rates declined over time; however, IgG antibodies remained more stable and persisted throughout the 12-month follow-up, whereas IgM antibodies became undetectable in most cases. Nevertheless, 12.5% of patients still had detectable IgM antibodies one year after symptom onset, whereas IgG seropositivity remained above 70%. Higher IgG titers were significantly associated with age ≥ 50 years, severe COVID-19, and SARS-CoV-2 pneumonia. Patients vaccinated before the final follow-up demonstrated a strong booster response with significantly higher IgG levels than unvaccinated individuals. In conclusion, symptomatic COVID-19 induces a durable humoral immune response that persists for at least 12 months. Hybrid immunity resulting from natural infection combined with vaccination appears to provide the strongest protection against SARS-CoV-2.

Biomarkers of protection against controlled human SARS-CoV-2 Delta variant breakthrough infection

Susceptibility to SARS-CoV-2 breakthrough infection in those with hybrid immunity is strongly associated with low levels of pre-existing antibody, but the diversity of immune markers associated with protection implies that additional benefits may be conferred by multi-pronged immunity.

A multimodal atlas of COVID-19 severity identifies hallmarks of dysregulated immunity 2258066

The alpha-variant wave of the COVID-19 pandemic provided a unique opportunity to study, at single-cell resolution, how near-universal exposure to the same pathogen can lead to either effective or dysfunctional immune responses in humans. We analyzed 2.5 million circulating immune cells from 428 patients across time points (840 PBMC samples), encompassing three contemporaneous SARS-CoV-2 cohorts: acutely infected patients at five WHO disease severity levels and three time points, patients from the first randomized control trial to study efficacy of tocilizumab in management of COVID-19, and convalescent patients three months after infection. We used linear modeling to integrate multiple data types – single-cell RNA-seq, CITE-seq, TCR and BCR sequencing, viral load measurements, viral neutralization assays, detection of 75 autoantibodies, HLA genotype data, and serum proteomics covering 1,463 targets – to derive the most comprehensive view to-date of the biological features of COVID-19 disease severity. We show that myeloid-derived suppressor cells (MDSCs) act as a key immunologic pivot point in severe COVID-19. Myeloid dysfunction is marked by impaired antigen presentation and drives a non-productive adaptive immune response. Severe disease is also linked to autoantibodies targeting type I interferons, specific HLA-DQB1 allelic variants, and serum IL-6 levels. Tocilizumab treatment eliminates CLU-expressing MDSCs and ISG-positive myeloid subsets, restores antigen presentation, and reactivates productive adaptive immunity. In convalescence 3-months post-infection, we found persistently high ICOS expression in regulatory T cells. Overall, we define distinct innate and adaptive host immune responses associated with acute, IL-6—responsive, and convalescent SARS-CoV-2 infection. Our multimodal and high-dimensional dataset with curated clinical metadata provides a foundational and clinically relevant resource for modeling host immune response biology in health and disease. We acknowledge the following funding sources: this work was supported by several training grants, including a NIAID grant T32AR007258 (to KS), three NHLBI grants 5T32HL116275-13 (to CC), 5T32HL129970-09 (to APN), and the K08HL157725 (to PS), as well as the American Heart Association Career Development Award (to PS). PS was also supported by the Brigham and Women’s Hospital Innovation Evergreen Fund. EY was supported by funding from the Stanford Medical Scholars program. RJX acknowledges supports from NIH DK43351 and U19AI142784. RJX and AR were supported by the Manton Foundation and the Klarman Cell Observatory. PJU was supported by Third Rock Ventures; Henry Gustav Floren Trust; Stanford Department of Medicine Team Science Program; Stanford Medicine Office of the Dean; and National Institutes of Health R01 grants AI175771 and AI182319-02. RPB acknowledges funding support from the Massachusetts General Hospital Executive Committee on Research, the American Lung Association, and the Broad Institute’s Next Generation Scholar award. MBG, MRF, and NH were supported by an American Lung Association COVID-19 Action Initiative grant. MBG and MRF were supported by a grant from the Executive Committee on Research at MGH. NH acknowledges was supported by NIH/NIAID U19 AI082630, a Chair and gift from Sandra, Sarah, and Arthur Irving. ACV acknowledges funding support from the COVID-19 Clinical Trials Pilot grant from the Executive Committee on Research at MGH; a COVID-19 Chan Zuckerberg Initiative grant (2020-216954); the funds from the Manton Foundation and the Klarman Family Foundation; the Broad Institute’s Next Generation Scholar award; the MGH Howard M. Goodman Fellowship; the National Institutes of Health (DP2CA247831); work at the Broad Institute was supported by a gift from an anonymous donor. Computational and Systems Immunology (COMP)

Prolonged SARS-CoV-2 infection in hematologic malignancies: clinical impact, risk factors and intra-host viral evolution

Introduction Prolonged SARS-CoV-2 infection in hematologic patients may go unrecognized. The aim of the study is to describe the incidence, risk factors, viral evolution and clinical outcomes of prolonged SARS-CoV-2 infection in patients with hematologic malignancies. Methods This is a prospective, observational study. We performed a longitudinal follow-up rRT-PCR with cycle threshold (Ct) assessment until negativization to 500 patients diagnosed with hematologic malignancies who suffered SARS-CoV-2 infection between March 2020 and August 2023. We considered prolonged COVID-19 to a positive rRT-PCR with a Ct <35 beyond 30 days after microbiological diagnosis with the same viral variant. Results Prolonged SARS-CoV-2 infection is a complication in 44.8% (156/348) of patients diagnosed with hematologic malignancies with a median time of rRT-PCR positivity of 58 days (IQR 43-88). Active treatment with bispecific antibodies, anti-CD20 antibodies, BTK inhibitors and immunosuppressive drugs for GvHD are significantly associated with prolonged viral shedding; as well as lack of vaccination, lesser booster vaccine doses, absence of anti-S seroconversion after immunization, severe acute infection and delayed antiviral treatment. A 56.4% (88/156) of patients exhibit a pattern of remitting and relapsing symptoms and fluctuant viral load. During those exacerbations, 70.5% of patients experienced an increase in the severity of the acute infection and 34% developed pneumopathy, particularly organizing pneumonia. Persistent COVID-19 caused 54.5% (85/156) of patients to interrupt and 19.9% (31/156) to suspend indefinitely their hematologic treatments. Viral intra-host mutations across the entire viral genome, predominantly within the spike were detected in most patients with prolonged COVID-19, especially in those who received anti-SARS-CoV-2 mAb as sotrovimab (E340, R346, K356) and tixagevimab/cilgavimab (R346, K444 and G446). These substitutions are associated with reduced viral susceptibility. Discussion Prolonged SARS-CoV-2 infection in hematologic patients is frequent and leads to persistent viral replication, significant morbidity and the emergence of intra-host viral mutations. Optimizing treatments and monitoring viral clearance are medical needs for high-risk patients.