scholarly journals Antibody-Dependent Enhancement of Severe Disease Is Mediated by Serum Viral Load in Pediatric Dengue Virus Infections

2020 ◽  
Vol 221 (11) ◽  
pp. 1846-1854 ◽  
Author(s):  
Jesse J Waggoner ◽  
Leah C Katzelnick ◽  
Raquel Burger-Calderon ◽  
Julia Gallini ◽  
Renee H Moore ◽  
...  
Keyword(s):  
Viral Load ◽  
Dengue Virus ◽  
Disease Severity ◽  
Antibody Titer ◽  
Severe Disease ◽  
Severe Dengue ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antibody Dependent Enhancement ◽  
Serum Viral Load ◽  
Antibody Titers

Abstract Background Low preexisting anti-dengue virus (DENV) antibody levels are associated with elevated disease severity. While antibody-dependent enhancement of dengue is thought to be driven by viral load, this has not been conclusively shown. We evaluated the association between preinfection anti-DENV antibody titers, viral load, and disease severity among 133 dengue cases in a Nicaraguan pediatric cohort study. Methods Viral load was quantified in acute-phase serum by real-time reverse transcription polymerase chain reaction and analyzed in relation to preinfection antibody titer (measured by inhibition enzyme-linked immunosorbent assay) and dengue severity, categorized using 3 definitions. Results Higher viral load was significantly associated with dengue severity; for each increase of 1.0 log10 copies/mL, the odds of severe dengue increased approximately 50%, regardless of severity definition. Viral load at presentation and the odds of severe disease were highest among patients with low to intermediate preinfection antibody titers and lowest among those with the highest antibody titers. We showed the effect of preinfection antibody titer on disease severity was mediated by viral load for each of 3 dengue severity outcomes. Conclusions This study demonstrates the association between preinfection anti-DENV antibody titer, serum viral load, and disease severity, and provides evidence for the mechanism of antibody-dependent enhancement in dengue cases.

scholarly journals Antibody-dependent enhancement of severe dengue disease in humans

Science ◽  
2017 ◽  
Vol 358 (6365) ◽  
pp. 929-932 ◽  
Author(s):  
Leah C. Katzelnick ◽  
Lionel Gresh ◽  
M. Elizabeth Halloran ◽  
Juan Carlos Mercado ◽  
Guillermina Kuan ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Severe Disease ◽  
Severe Dengue ◽  
Antibody Dependent Enhancement ◽  
Dengue Disease ◽  
Symptomatic Disease ◽  
Immune Correlates ◽  
Antibody Titers ◽  
Approaches To Study

For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.

scholarly journals Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

2016 ◽  
Vol 113 (3) ◽  
pp. 728-733 ◽  
Author(s):  
Leah C. Katzelnick ◽  
Magelda Montoya ◽  
Lionel Gresh ◽  
Angel Balmaseda ◽  
Eva Harris
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Secondary Infection ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
Severe Dengue ◽  
Symptomatic Infection ◽  
Denv Serotypes ◽  
Antibody Titers

The four dengue virus serotypes (DENV1–4) are mosquito-borne flaviviruses that infect ∼390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.

scholarly journals Dengue Fever and Severe Dengue in Barbados, 2008–2016

2020 ◽  
Vol 5 (2) ◽  
pp. 68
Author(s):  
Kirk Osmond Douglas ◽  
Sudip Kumar Dutta ◽  
Byron Martina ◽  
Fatih Anfasa ◽  
T. Alafia Samuels ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Fever ◽  
Small Sample Size ◽  
Health Planning ◽  
Case Fatality ◽  
Small Sample ◽  
Severe Dengue ◽  
Medical Attention ◽  
Enzyme Linked Immunosorbent Assay ◽  
Virus Serotype

Analysis of the temporal, seasonal and demographic distribution of dengue virus (DENV) infections in Barbados was conducted using national surveillance data from a total of 3994 confirmed dengue cases. Diagnosis was confirmed either by DENV–specific real time reverse transcriptase polymerase chain reaction (rRT–PCR), or non–structural protein 1 (NS1) antigen or enzyme linked immunosorbent assay (ELISA) tests; a case fatality rate of 0.4% (10/3994) was observed. The dengue fever (DF) prevalence varied from 27.5 to 453.9 cases per 100,000 population among febrile patients who sought medical attention annually. DF cases occurred throughout the year with low level of transmission observed during the dry season (December to June), then increased transmission during rainy season (July to November) peaking in October. Three major dengue epidemics occurred in Barbados during 2010, 2013 and possibly 2016 with an emerging three–year interval. DF prevalence among febrile patients who sought medical attention overall was highest among the 10–19 years old age group. The highest DF hospitalisation prevalence was observed in 2013. Multiple serotypes circulated during the study period and Dengue virus serotype 2 (DENV–2) was the most prevalent serotype during 2010, whilst DENV–1 was the most prevalent serotype in 2013. Two DENV–1 strains from the 2013 DENV epidemic were genetically more closely related to South East Asian strains, than Caribbean or South American strains, and represent the first ever sequencing of DENV strains in Barbados. However, the small sample size (n = 2) limits any meaningful conclusions. DF prevalence was not significantly different between females and males. Public health planning should consider DENV inter–epidemic periodicity, the current COVID–19 pandemic and similar clinical symptomology between DF and COVID–19. The implementation of routine sequencing of DENV strains to obtain critical data can aid in battling DENV epidemics in Barbados.

scholarly journals An Antigen Capture Enzyme-Linked Immunosorbent Assay Reveals High Levels of the Dengue Virus Protein NS1 in the Sera of Infected Patients

2000 ◽  
Vol 38 (3) ◽  
pp. 1053-1057 ◽  
Author(s):  
Paul R. Young ◽  
Paige A. Hilditch ◽  
Cheryl Bletchly ◽  
Wendy Halloran
Keyword(s):  
Monoclonal Antibodies ◽  
Dengue Virus ◽  
Acute Phase ◽  
Immunosorbent Assay ◽  
Nonstructural Protein ◽  
Surrogate Marker ◽  
Detection Sensitivity ◽  
Severe Dengue ◽  
Clinical Samples ◽  
Enzyme Linked Immunosorbent Assay

We describe the development of a capture enzyme-linked immunosorbent assay for the detection of the dengue virus nonstructural protein NS1. The assay employs rabbit polyclonal and monoclonal antibodies as the capture and detection antibodies, respectively. Immunoaffinity-purified NS1 derived from dengue 2 virus-infected cells was used as a standard to establish a detection sensitivity of approximately 4 ng/ml for an assay employing monoclonal antibodies recognizing a dengue 2 serotype-specific epitope. A number of serotype cross-reactive monoclonal antibodies were also shown to be suitable probes for the detection of NS1 expressed by the remaining three dengue virus serotypes. Examination of clinical samples demonstrated that the assay was able to detect NS1 with minimal interference from serum components at the test dilutions routinely used, suggesting that it could form the basis of a useful additional diagnostic test for dengue virus infection. Furthermore, quantitation of NS1 levels in patient sera may prove to be a valuable surrogate marker for viremia. Surprisingly high levels of NS1, as much as 15 μg/ml, were found in acute-phase sera taken from some of the patients experiencing serologically confirmed dengue 2 virus secondary infections but was not detected in the convalescent sera of these patients. In contrast, NS1 could not be detected in either acute-phase or convalescent serum samples taken from patients with serologically confirmed primary infection. The presence of high levels of secreted NS1 in the sera of patients experiencing secondary dengue virus infections, and in the context of an anamnestic antibody response, suggests that NS1 may contribute significantly to the formation of the circulating immune complexes that are suspected to play an important role in the pathogenesis of severe dengue disease.

scholarly journals Current Understanding of the Pathogenesis of Dengue Virus Infection

2020 ◽  
Author(s):  
Puneet Bhatt ◽  
Sasidharan Pillai Sabeena ◽  
Muralidhar Varma ◽  
Govindakarnavar Arunkumar
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Virus Infection ◽  
Dengue Virus ◽  
Genetic Factors ◽  
Host Immune Response ◽  
Severe Dengue ◽  
Ns1 Protein ◽  
Dengue Virus Infection ◽  
Antibody Dependent Enhancement

AbstractThe pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. Fcγ receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability. Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. Dengue infection can lead to the generation of autoantibodies against DENV NS1antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. This review article highlights the various factors responsible for the pathogenesis of dengue and also highlights the recent advances in the field related to biomarkers which can be used in future for predicting severe disease outcome.

scholarly journals IL-6 and IL-10 Levels, Rather Than Viral Load and Neutralizing Antibody Titers, Determine the Fate of Patients With Severe Fever With Thrombocytopenia Syndrome Virus Infection in South Korea

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeong Rae Yoo ◽  
Tae-Jin Kim ◽  
Sang Taek Heo ◽  
Kyung-Ah Hwang ◽  
Hyunjoo Oh ◽  
...  
Keyword(s):  
Viral Load ◽  
Close Contact ◽  
Multiorgan Failure ◽  
Severe Disease ◽  
Elevated Serum ◽  
Gastrointestinal Symptoms ◽  
Neutralizing Antibody ◽  
Haemaphysalis Longicornis ◽  
Antibody Titers ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne viral disease, and most SFTS virus (SFTSV) infections occur via bites from the tick Haemaphysalis longicornis; however, SFTSV transmission can also occur through close contact with an infected patient. SFTS is characterized by acute high fever, thrombocytopenia, leukopenia, elevated serum hepatic enzyme levels, gastrointestinal symptoms, and multiorgan failure and has a 16.2 to 30% mortality rate. In this study, we found that age, dyspnea rates, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, multiorgan dysfunction score (MODS), viral load, IL-6 levels, and IL-10 levels were higher in patients with fatal disease than in patients with nonfatal disease during the initial clinical course of SFTS. In addition, we found that IL-6 and IL-10 levels, rather than viral load and neutralizing antibody titers, in patients with an SFTSV infection strongly correlated with outcomes (for severe disease with an ultimate outcome of recovery or death).

scholarly journals Differential Association of Viral Dynamics With Disease Severity Depending on Patients’ Age Group in COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuri Kim ◽  
Shinhyea Cheon ◽  
Hyeongseok Jeong ◽  
Uni Park ◽  
Na-Young Ha ◽  
...  
Keyword(s):  
Viral Load ◽  
Elderly Patients ◽  
Disease Severity ◽  
Acute Phase ◽  
Inflammatory Responses ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
The Elderly ◽  
Clinical Severity ◽  
Younger Patients

Despite a clear association of patient’s age with COVID-19 severity, there has been conflicting data on the association of viral load with disease severity. Here, we investigated the association of viral load dynamics with patient’s age and severity of COVID-19 using a set of respiratory specimens longitudinally collected (mean: 4.8 times/patient) from 64 patients with broad distribution of clinical severity and age during acute phase. Higher viral burden was positively associated with inflammatory responses, as assessed by IL-6, C-reactive protein, and lactate dehydrogenase levels in patients’ plasma collected on the same day, primarily in the younger cohort (≤59 years old) and in mild cases of all ages, whereas these were barely detectable in elderly patients (≥60 years old) with critical disease. In addition, viral load dynamics in elderly patients were not significantly different between mild and critical cases, even though more enhanced inflammation was consistently observed in the elderly group when compared to the younger group during the acute phase of infection. The positive correlation of viral load with disease severity in younger patients may explain the increased therapeutic responsiveness to current antiviral drugs and neutralizing antibody therapies in younger patients compared to elderly patients. More careful intervention against aging-associated inflammation might be required to mitigate severe disease progression and reduce fatality in COVID-19 patients more than 60 years old.

scholarly journals Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242917
Author(s):  
Tobias Schlesinger ◽  
Benedikt Weißbrich ◽  
Florian Wedekink ◽  
Quirin Notz ◽  
Johannes Herrmann ◽  
...  
Keyword(s):  
Intensive Care ◽  
Viral Load ◽  
Disease Severity ◽  
Quantitative Polymerase Chain Reaction ◽  
Antiviral Treatment ◽  
Antibody Detection ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intensive Care Treatment ◽  
Blood Samples ◽  
Tracheal Aspirates

Background The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). Methods This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. Results Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). Conclusions COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.

scholarly journals An enzyme-linked immunosorbent assay for platelet compatibility testing

Blood ◽  
1983 ◽  
Vol 62 (4) ◽  
pp. 744-749 ◽  
Author(s):  
JD Tamerius ◽  
JG Curd ◽  
P Tani ◽  
R McMillan
Keyword(s):  
Antibody Titer ◽  
Immunosorbent Assay ◽  
Clinical Laboratory ◽  
Clinical Problem ◽  
Enzyme Linked Immunosorbent Assay ◽  
Microtiter Plates ◽  
Volunteer Donor ◽  
Antibody Titers ◽  
Test Serum ◽  
Selection Of

Abstract The selection of platelet donors for patients who are refractory to random donor platelets often presents a difficult clinical problem. We describe an enzyme-linked immunosorbent assay (ELISA) for evaluating alloantibodies in refractory patients. Platelets from prospective donors are immobilized on microtiter plates and, after incubation with test serum and washing, platelet-bound IgG is detected with enzyme- linked anti-human IgG. Platelets from 46 prospective donors were tested. Twenty-two were judged compatible (reciprocal of the antibody titer less than 16) and, of these, 15 were used as platelet donors; each gave a measurable platelet increment after transfusion. The magnitude of the response was roughly proportional to the assay results. Platelets from donors giving antibody titers less than 4 resulted in platelet increments at 1 hr ranging from 4,890 to 22,200 (median 12,600), while platelets from donors giving titers of 8 or 16 resulted in lesser increments (550–4548). Conversely, 5 of the 24 patients found incompatible by the assay (titer greater than 16) gave no platelet increment, and in 3 instances, the recipient developed fever and chills after the transfusion. The assay is sensitive, simple, and adaptable to the clinical laboratory. Platelets from volunteer donor panels can be plated and stored for up to 6 mo.

Sign in / Sign up

Export Citation Format

Share Document