LB-1Treatment with Oral ALS-008176, a Nucleoside Analog, Rapidly Reduces RSV Viral Load and Clinical Disease Severity in a Healthy Volunteer Challenge Study

ABSTRACTDespite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms.IMPORTANCEThis study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

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Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children

Influenza and Other Respiratory Viruses ◽

10.1111/j.1750-2659.2011.00265.x ◽

2011 ◽

Vol 6 (1) ◽

pp. 71-77 ◽

Cited By ~ 108

Author(s):

Emily T. Martin ◽

Jane Kuypers ◽

Anna Wald ◽

Janet A. Englund

Keyword(s):

Viral Load ◽

Disease Severity ◽

Respiratory Infections ◽

Clinical Disease ◽

Hospitalized Children

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Quantification of dengue virus specific T cell responses and correlation with viral load and clinical disease severity in acute dengue infection

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0006540 ◽

2018 ◽

Vol 12 (10) ◽

pp. e0006540 ◽

Cited By ~ 20

Author(s):

Dulharie T. Wijeratne ◽

Samitha Fernando ◽

Laksiri Gomes ◽

Chandima Jeewandara ◽

Anushka Ginneliya ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Dengue Virus ◽

Disease Severity ◽

Dengue Infection ◽

T Cell Responses ◽

Clinical Disease ◽

Cell Responses

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Correlation of Pandemic (H1N1) 2009 Viral Load with Disease Severity and Prolonged Viral Shedding in Children

Emerging Infectious Diseases ◽

10.3201/eid1608.091918 ◽

2010 ◽

Vol 16 (8) ◽

pp. 1265-1272 ◽

Cited By ~ 77

Author(s):

Chung-Chen Li ◽

Lin Wang ◽

Hock-Liew Eng ◽

Huey-Ling You ◽

Ling-Sai Chang ◽

...

Keyword(s):

Viral Load ◽

Disease Severity ◽

Pandemic H1n1 ◽

Viral Shedding ◽

Pandemic H1n1 2009

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Viral Dynamics and Real-Time RT-PCR Ct Values Correlation with Disease Severity in COVID-19

Diagnostics ◽

10.3390/diagnostics11061091 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1091

Author(s):

Ali A. Rabaan ◽

Raghavendra Tirupathi ◽

Anupam A Sule ◽

Jehad Aldali ◽

Abbas Al Mutair ◽

...

Keyword(s):

Viral Load ◽

Real Time ◽

Disease Severity ◽

False Negative ◽

Influential Factors ◽

Confirmatory Test ◽

Acid Extraction ◽

Rt Pcr ◽

Viral Kinetics ◽

Ct Value

Real-time RT-PCR is considered the gold standard confirmatory test for coronavirus disease 2019 (COVID-19). However, many scientists disagree, and it is essential to understand that several factors and variables can cause a false-negative test. In this context, cycle threshold (Ct) values are being utilized to diagnose or predict SARS-CoV-2 infection. This practice has a significant clinical utility as Ct values can be correlated with the viral load. In addition, Ct values have a strong correlation with multiple haematological and biochemical markers. However, it is essential to consider that Ct values might be affected by pre-analytic, analytic, and post-analytical variables such as collection technique, specimen type, sampling time, viral kinetics, transport and storage conditions, nucleic acid extraction, viral RNA load, primer designing, real-time PCR efficiency, and Ct value determination method. Therefore, understanding the interpretation of Ct values and other influential factors could play a crucial role in interpreting viral load and disease severity. In several clinical studies consisting of small or large sample sizes, several discrepancies exist regarding a significant positive correlation between the Ct value and disease severity in COVID-19. In this context, a revised review of the literature has been conducted to fill the knowledge gaps regarding the correlations between Ct values and severity/fatality rates of patients with COVID-19. Various databases such as PubMed, Science Direct, Medline, Scopus, and Google Scholar were searched up to April 2021 by using keywords including “RT-PCR or viral load”, “SARS-CoV-2 and RT-PCR”, “Ct value and viral load”, “Ct value or COVID-19”. Research articles were extracted and selected independently by the authors and included in the present review based on their relevance to the study. The current narrative review explores the correlation of Ct values with mortality, disease progression, severity, and infectivity. We also discuss the factors that can affect these values, such as collection technique, type of swab, sampling method, etc.

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Adenovirus viremia may predict adenovirus pneumonia severity in immunocompetent children

BMC Infectious Diseases ◽

10.1186/s12879-021-05903-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ruimu Zhang ◽

Hongmei Wang ◽

Shufeng Tian ◽

Jikui Deng

Keyword(s):

Risk Factors ◽

Viral Load ◽

Disease Severity ◽

Mycoplasma Pneumoniae ◽

Quantitative Polymerase Chain Reaction ◽

Univariate Analysis ◽

Clinical Manifestations ◽

Pneumonia Severity ◽

Adenovirus Pneumonia ◽

Blood Viral Load

Abstract Background Previous studies have demonstrated an association between adenovirus viremia and disease severity in immunocompromised children. However, few studies have focused on this association in immunocompetent children. This study explored the association between adenovirus viremia and adenovirus pneumonia severity in immunocompetent children. Methods We performed a retrospective, observational study of immunocompetent children with adenovirus pneumonia admitted to Shenzhen Children’s Hospital in Shenzhen, China. Pneumonia was classified as severe or mild based on the Chinese guideline for the classification of pneumonia severity. Serum samples from all the children included in the study were tested for adenovirus DNA with a quantitative polymerase chain reaction. Clinical manifestations, laboratory examinations, and disease severity were compared between children with severe and mild pneumonia. Results A total of 111 immunocompetent children with adenovirus pneumonia (60 severe, 51 mild) were included. The median age was 40 months, and 64 patients were male. Five patients were admitted to the intensive care unit, and two underwent endotracheal intubation. All patients were discharged after recovery or improvement. Univariate analysis and binary logistic regression analysis showed that leukocytosis (OR = 1.1; 95% CI: 1.0 to 1.2; P = 0.033), co-infection with Mycoplasma pneumoniae (OR = 5.0; 95% CI: 2.1 to 12.3; P < 0.001), and high blood viral load (OR = 1.5; 95% CI: 1.2 to 2.0; P = 0.001) may be risk factors for severe adenovirus pneumonia. Conclusions Leukocytosis, co-infection with Mycoplasma pneumoniae, and high blood viral load may be risk factors for severe adenovirus pneumonia in immunocompetent children. Blood viral load may predict pneumonia severity.

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The Characterization of Disease Severity Associated IgG Subclasses Response in COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.632814 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huanle Luo ◽

Tingting Jia ◽

Jiamin Chen ◽

Shike Zeng ◽

Zengzhao Qiu ◽

...

Keyword(s):

Viral Load ◽

Disease Severity ◽

Young Patients ◽

Neutralizing Antibody ◽

Igg Subclasses ◽

Nasopharyngeal Swab ◽

Obvious Effect ◽

Old Patients ◽

Biological Sex ◽

Specific Igg

Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1β was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.

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Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality

10.1101/2021.01.04.21249236 ◽

2021 ◽

Author(s):

Julio Silva ◽

Carolina Lucas ◽

Maria Sundaram ◽

Benjamin Israelow ◽

Patrick Wong ◽

...

Keyword(s):

Viral Load ◽

Disease Severity ◽

T Cell Subsets ◽

Temporal Association ◽

Strongly Correlated ◽

Immunological Parameters ◽

Viral Loads ◽

Patient Demographics ◽

Over Time

While several clinical and immunological parameters correlate with disease severity and mortality in SARS-CoV-2 infection, work remains in identifying unifying correlates of coronavirus disease 2019 (COVID-19) that can be used to guide clinical practice. Here, we examine saliva and nasopharyngeal (NP) viral load over time and correlate them with patient demographics, and cellular and immune profiling. We found that saliva viral load was significantly higher in those with COVID-19 risk factors; that it correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time (AUC=0.90). A comprehensive analysis of immune factors and cell subsets revealed strong predictors of high and low saliva viral load, which were associated with increased disease severity or better overall outcomes, respectively. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. Higher saliva viral loads strongly correlated with the progressive depletion of platelets, lymphocytes, and effector T cell subsets including circulating follicular CD4 T cells (cTfh). Anti-spike (S) and anti-receptor binding domain (RBD) IgG levels were negatively correlated with saliva viral load showing a strong temporal association that could help distinguish severity and mortality in COVID-19. Finally, patients with fatal COVID-19 exhibited higher viral loads, which correlated with the depletion of cTfh cells, and lower production of anti-RBD and anti-S IgG levels. Together these results demonstrated that viral load – as measured by saliva but not nasopharyngeal — is a dynamic unifying correlate of disease presentation, severity, and mortality over time.

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