scholarly journals Neutralizing Antibody Therapeutics for COVID-19

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 628
Author(s):  
Aeron C. Hurt ◽  
Adam K. Wheatley
Keyword(s):  
High Risk ◽  
Neutralizing Antibodies ◽  
Controlled Trial ◽  
Antiviral Treatment ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Supplemental Oxygen ◽  
European Medicines Agency ◽  
Global Public Health ◽  
Public Health Burden

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic has resulted in a significant global public health burden, leading to an urgent need for effective therapeutic strategies. In this article, we review the role of SARS-CoV-2 neutralizing antibodies (nAbs) in the clinical management of COVID-19 and provide an overview of recent randomized controlled trial data evaluating nAbs in the ambulatory, hospitalized and prophylaxis settings. Two nAb cocktails (casirivimab/imdevimab and bamlanivimab/etesevimab) and one nAb monotherapy (bamlanivimab) have been granted Emergency Use Authorization by the US Food and Drug Administration for the treatment of ambulatory patients who have a high risk of progressing to severe disease, and the European Medicines Agency has similarly recommended both cocktails and bamlanivimab monotherapy for use in COVID-19 patients who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19. Efficacy of nAbs in hospitalized patients with COVID-19 has been varied, potentially highlighting the challenges of antiviral treatment in patients who have already progressed to severe disease. However, early data suggest a promising prophylactic role for nAbs in providing effective COVID-19 protection. We also review the risk of treatment-emergent antiviral resistant “escape” mutants and strategies to minimize their occurrence, discuss the susceptibility of newly emerging SARS-COV-2 variants to nAbs, as well as explore administration challenges and ways to improve patient access.

scholarly journals Safety and immunogenicity of inactivated SARS-CoV-2 vaccine in high-risk occupational population: a randomized, parallel, controlled clinical trial

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yongliang Feng ◽  
Jing Chen ◽  
Tian Yao ◽  
Yue Chang ◽  
Xiaoqing Li ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Neutralizing Antibodies ◽  
Health Care Systems ◽  
Controlled Trial ◽  
Geometric Mean ◽  
Neutralizing Antibody ◽  
Shanxi Province ◽  
Controlled Clinical Trial ◽  
Clinical Trial Registry

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (COVID-19) have a substantial burden on health-care systems around the world. This is a randomized parallel controlled trial for assessment of the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine, aiming to determine an appropriate vaccination interval of the vaccine for high-risk occupational population. Methods In an ongoing randomized, parallel, controlled phase IV trial between January and May 2021 in Taiyuan City, Shanxi Province, China, we randomly assigned the airport ground staff and public security officers aged 18 to 59 years to receive two doses of inactivated SARS-CoV-2 vaccine at 14 days, 21 days, or 28 days. The serum neutralizing antibody to live SARS-CoV-2 was performed at baseline and 28 days after immunization. Long-term data are being collected. The primary immunogenicity endpoints were neutralization antibody seroconversion and geometric mean titer (GMT) at 28 days after the second dose. Analysis of variance (ANOVA), chi-square, and logistic regression analysis were used for data analysis. Results A total of 809 participants underwent randomization and received two doses of injections: 270, 270, 269 in the 0–14, 0–21, and 0–28 vaccination group, respectively. By day 28 after the second injection, SARS-CoV-2 neutralizing antibody of GMT was 98.4 (95% CI: 88.4–108.4) in the 0–14 group, which was significantly lower compared with 134.4 (95% CI: 123.1–145.7) in the 0–21 group (P < 0.001 vs 0–14 group) and 145.5 (95% CI: 131.3–159.6) in the 0–28 group (P < 0.001 vs 0–14 group), resulting in the seroconversion rates to neutralizing antibodies (GMT ≥ 16) of 100.0% for all three groups, respectively. The intention-to-treat (ITT) analysis yielded similar results. All reported adverse reactions were mild. Conclusions Both a two-dose of inactivated SARS-CoV-2 vaccine at 0–21 days and 0–28 days regimens significantly improved SARS-CoV-2 neutralizing antibody level compared to the 0–14 days regimen in high-risk occupational population, with seroconversion rates of 100.0%. Trial registration Chinese Clinical Trial Registry, ChiCTR2100041705, ChiCTR2100041706. Registered 1 January 2021, www.chictr.org.cn. Graphical Abstract

scholarly journals Convergent structural features of respiratory syncytial virus neutralizing antibodies and plasticity of the site V epitope on prefusion F

2020 ◽  
Vol 16 (11) ◽  
pp. e1008943
Author(s):  
Wayne Harshbarger ◽  
Sai Tian ◽  
Newton Wahome ◽  
Ankita Balsaraf ◽  
Deep Bhattacharya ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Structural Features ◽  
Global Public Health ◽  
Public Health Burden ◽  
Functional Studies ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is a global public health burden for which no licensed vaccine exists. To aid vaccine development via increased understanding of the protective antibody response to RSV prefusion glycoprotein F (PreF), we performed structural and functional studies using the human neutralizing antibody (nAb) RSB1. The crystal structure of PreF complexed with RSB1 reveals a conformational, pre-fusion specific site V epitope with a unique cross-protomer binding mechanism. We identify shared structural features between nAbs RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same PreF site of vulnerability. Importantly, RSB1-like nAbs were induced upon immunization with PreF in naturally-primed cattle. Together, this work reveals new details underlying the immunogenicity of site V and further supports PreF-based vaccine development efforts.

scholarly journals Effect of the Neutralizing SARS-CoV-2 Antibody Sotrovimab in Preventing Progression of COVID-19: A Randomized Clinical Trial

2021 ◽  
Author(s):  
Anil Gupta ◽  
Yaneicy Gonzalez-Rojas ◽  
Erick Juarez ◽  
Manuel Crespo ◽  
Jaynier Moya ◽  
...  
Keyword(s):  
High Risk ◽  
Emergency Room ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Supplemental Oxygen ◽  
Secondary Outcome ◽  
Effective Treatment Option ◽  
Double Blind ◽  
Increased Risk ◽  
High Flow Oxygen

Importance: Older patients and those with underlying comorbidities infected with SARS-CoV-2 may be at increased risk of hospitalization and death from COVID-19. Sotrovimab is a neutralizing antibody designed for treatment of high-risk patients to prevent COVID-19 progression. Objective: To evaluate the efficacy and safety of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. Design: Randomized, double-blind, multicenter, placebo-controlled, phase 3 study. Setting: 57 centers in 5 countries. Participants: Nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for disease progression. Intervention: Patients were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with COVID-19 progression, defined as all-cause hospitalization longer than 24 hours for acute illness management or death through day 29. Key secondary outcomes included the proportion of patients with COVID-19 progression, defined as emergency room visit, hospitalization of any duration, or death, and proportion of patients developing severe/critical respiratory COVID-19 requiring supplemental oxygen. Results: Among 1057 patients randomized (sotrovimab, 528; placebo, 529), all-cause hospitalization longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) by 79% (95% CI, 50% to 91%; P<.001). Secondary outcome results further demonstrated the effect of sotrovimab in reducing emergency room visits, hospitalization of any duration, or death, which was reduced by 66% (95% CI, 37% to 81%; P<.001), and severe/critical respiratory COVID-19, which was reduced by 74% (95% CI, 41% to 88%; P=.002). No patients receiving sotrovimab required high-flow oxygen, oxygen via nonrebreather mask, or mechanical ventilation compared with 14 patients receiving placebo. The proportion of patients reporting adverse events was similar between treatment groups; sotrovimab was well tolerated, and no safety concerns were identified. Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19, a single 500-mg intravenous dose of sotrovimab prevented progression of COVID-19, with a reduction in hospitalization and need for supplemental oxygen. Sotrovimab is a well-tolerated, effective treatment option for patients at high risk for severe morbidity and mortality from COVID-19.

scholarly journals Titers of Neutralizing Antibodies against SARS-CoV-2 Are Independent of Symptoms of Non-Severe COVID-19 in Young Adults

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 284
Author(s):  
Hulda R. Jonsdottir ◽  
Michel Bielecki ◽  
Denise Siegrist ◽  
Thomas W. Buehrer ◽  
Roland Züst ◽  
...  
Keyword(s):  
Young Adults ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Neutralization Assay ◽  
Asymptomatic Infection ◽  
Homogeneous Population ◽  
Humoral Immune ◽  
Antibody Titers

Neutralizing antibodies are an important part of the humoral immune response to SARS-CoV-2. It is currently unclear to what extent such antibodies are produced after non-severe disease or asymptomatic infection. We studied a cluster of SARS-CoV-2 infections among a homogeneous population of 332 predominantly male Swiss soldiers and determined the neutralizing antibody response with a serum neutralization assay using a recombinant SARS-CoV-2-GFP. All patients with non-severe COVID-19 showed a swift humoral response within two weeks after the onset of symptoms, which remained stable for the duration of the study. One month after the outbreak, titers in COVID-19 convalescents did not differ from the titers of asymptomatically infected individuals. Furthermore, symptoms of COVID-19 did not correlate with neutralizing antibody titers. Therefore, we conclude that asymptomatic infection can induce the same humoral immunity as non-severe COVID-19 in young adults.

scholarly journals Emerging Antimicrobial-Resistant High-Risk Klebsiella pneumoniae Clones ST307 and ST147

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Gisele Peirano ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
Johann D. D. Pitout
Keyword(s):  
Public Health ◽  
High Risk ◽  
Klebsiella Pneumoniae ◽  
The United States ◽  
Medical Community ◽  
Global Public Health ◽  
African Countries ◽  
Content Type ◽  
Public Health Burden ◽  
Worldwide Distribution

ABSTRACT There is an enormous global public health burden due to antimicrobial-resistant (AMR) Klebsiella pneumoniae high-risk clones. K. pneumoniae ST307 and ST147 are recent additions to the family of successful clones in the species. Both clones likely emerged in Europe during the early to mid-1990s and, in a relatively short time, became prominent global pathogens, spreading to all continents (with the exception of Antarctica). ST307 and ST147 consist of multiple clades/clusters and are associated with various carbapenemases (i.e., KPCs, NDMs, OXA-48-like, and VIMs). ST307 is endemic in Italy, Colombia, the United States (Texas), and South Africa, while ST147 is endemic in India, Italy, Greece, and certain North African countries. Both clones have been introduced into regions of nonendemicity, leading to worldwide nosocomial outbreaks. Genomic studies showed ST307 and ST147 contain identical gyrA and parC mutations and likely obtained plasmids with blaCTX-M-15 during the early to mid-2000s, which aided in their global distribution. ST307 and ST147 then acquired plasmids with various carbapenemases during the late 2000s, establishing themselves as important AMR pathogens in certain regions. Both clones are likely underreported due to restricted detection methodologies. ST307 and ST147 have the ability to become major threats to public health due to their worldwide distribution, ability to cause serious infections, and association with AMR, including panresistance. The medical community at large, especially those concerned with antimicrobial resistance, should be aware of the looming threat posed by emerging AMR high-risk clones such as K. pneumoniae ST307 and ST147.

scholarly journals Structures of Two Human Astrovirus Capsid/Neutralizing Antibody Complexes Reveal Distinct Epitopes and Inhibition of Virus Attachment to Cells

2021 ◽  
Author(s):  
Lena Ricemeyer ◽  
Nayeli Aguilar-Hernández ◽  
Tomás López ◽  
Rafaela Espinosa ◽  
Sarah Lanning ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Neutralizing Antibody ◽  
Host Cells ◽  
Viral Gastroenteritis ◽  
Receptor Binding Site ◽  
Virus Attachment ◽  
Human Astroviruses ◽  
Human Astrovirus

Human astrovirus is an important cause of viral gastroenteritis worldwide. Young children, the elderly, and the immunocompromised are especially at risk for contracting severe disease. However, no vaccines exist to combat human astrovirus infection. Evidence points to the importance of antibodies in enabling protection of healthy adults from reinfection. To develop an effective subunit vaccine that broadly protects against diverse astrovirus serotypes, we must understand how neutralizing antibodies target the capsid surface at the molecular level. Here, we report the structures of the human astrovirus capsid spike domain bound to two neutralizing monoclonal antibodies. These antibodies bind two distinct conformational epitopes on the spike surface. We add to existing evidence that the human astrovirus capsid spike contains a receptor-binding domain and demonstrate that both antibodies neutralize human astrovirus by blocking virus attachment to host cells. We identify patches of conserved amino acids that overlap or border the antibody epitopes and may constitute a receptor-binding site. Our findings provide a basis to develop therapies that prevent and treat human astrovirus gastroenteritis. Importance Human astroviruses infect nearly every person in the world during childhood and cause diarrhea, vomiting, and fever. Despite the prevalence of this virus, little is known about how antibodies block virus infection. Here, we determined crystal structures of the astrovirus capsid protein in complex with two virus-neutralizing antibodies. We show that the antibodies bind two distinct sites on the capsid spike domain; however, both antibodies block virus attachment to human cells. Importantly, our findings support the use of the human astrovirus capsid spike as an antigen in a subunit-based vaccine to prevent astrovirus disease.

scholarly journals LB2. Safety and Efficacy of Combination SARS-CoV-2 Monoclonal Neutralizing Antibodies (mAb) BRII-196 and BRII-198 in Non-Hospitalized COVID-19 Patients

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S807-S808
Author(s):  
Teresa H Evering ◽  
Mark Giganti ◽  
Kara W Chew ◽  
Michael Hughes ◽  
Carlee Moser ◽  
...  
Keyword(s):  
High Risk ◽  
Symptom Onset ◽  
Interim Analysis ◽  
Neutralizing Antibodies ◽  
Severe Disease ◽  
Panel Member ◽  
The Philippines ◽  
Research Support ◽  
Review Panel ◽  
Research Grant

Abstract Background SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease. Disclosures Kara W. Chew, MD, MS, Amgen (Individual(s) Involved: Self): Grant/Research Support; Merck Sharp & Dohme (Individual(s) Involved: Self): Grant/Research Support David Alain Wohl, MD, Gilead Sciences (Individual(s) Involved: Self): Advisor or Review Panel member, Consultant, Research Grant or Support, Scientific Research Study Investigator; Janssen (Individual(s) Involved: Self): Advisor or Review Panel member; Merck (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support; ViiV (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) David A. Margolis, MD MPH, Brii Biosciences (Employee) Courtney Fletcher, Pharm.D., National Institute of Allergy and Infectious Diseases, NIH (Grant/Research Support) Davey Smith, M.D., Linear Therapies, Matrix Biomed, Bayer (Consultant, Shareholder) Eric Daar, Gilead (Consultant, Grant/Research Support)Merck (Consultant)ViiV (Consultant, Grant/Research Support)

scholarly journals Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications

2020 ◽  
Author(s):  
Fan Wu ◽  
Aojie Wang ◽  
Mei Liu ◽  
Qimin Wang ◽  
Jun Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Time Course ◽  
Lentiviral Vector ◽  
Young Patients ◽  
Clinical Manifestations ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Effective Vaccine ◽  
Global Public Health

BackgroundThe COVID-19 pandemic caused by SARS-CoV-2 coronavirus threatens global public health. Currently, neutralizing antibodies (NAbs) versus this virus are expected to correlate with recovery and protection of this disease. However, the characteristics of these antibodies have not been well studied in association with the clinical manifestations in patients.MethodsPlasma collected from 175 COVID-19 recovered patients with mild symptoms were screened using a safe and sensitive pseudotyped-lentiviral-vector-based neutralization assay. Spike-binding antibody in plasma were determined by ELISA using RBD, S1, and S2 proteins of SARS-CoV-2. The levels and the time course of SARS-CoV-2-specific NAbs and the spike-binding antibodies were monitored at the same time.FindingsSARS-CoV-2 NAbs were unable to cross-reactive with SARS-CoV virus. SARS-CoV-2-specific NAbs were detected in patients from day 10-15 after the onset of the disease and remained thereafter. The titers of NAb among these patients correlated with the spike-binding antibodies targeting S1, RBD, and S2 regions. The titers of NAbs were variable in different patients. Elderly and middle-age patients had significantly higher plasma NAb titers (P<0.0001) and spike-binding antibodies (P=0.0003) than young patients. Notably, among these patients, there were ten patients whose NAb titers were under the detectable level of our assay (ID50: < 40); while in contrast, two patients, showed very high titers of NAb, with ID50 :15989 and 21567 respectively. The NAb titers were positive correlated with plasma CRP levels but negative correlated with the lymphocyte counts of patients at the time of admission, indicating an association between humoral response and cellular immune response.InterpretationThe variations of SARS-CoV-2 specific NAbs in recovered COVID-19 patients may raise the concern about the role of NAbs on disease progression. The correlation of NAb titers with age, lymphocyte counts, and blood CRP levels suggested that the interplay between virus and host immune response in coronavirus infections should be further explored for the development of effective vaccine against SARS-CoV-2 virus. Furthermore, titration of NAb is helpful prior to the use of convalescent plasma for prevention or treatment.FundingMinistry of Science and Technology of China, National Natural Science Foundation of China, Shanghai Municipal Health Commission, and Chinese Academy of Medical Sciences

scholarly journals Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial)

2020 ◽  
Author(s):  
Anup Agarwal ◽  
Aparna Mukherjee ◽  
Gunjan Kumar ◽  
Pranab Chatterjee ◽  
Tarun Bhatnagar ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Phase Ii ◽  
Neutralizing Antibodies ◽  
Therapeutic Option ◽  
Controlled Trial ◽  
Severe Disease ◽  
Real Life ◽  
Open Label ◽  
Randomized Controlled ◽  
And Control

Objectives: Convalescent plasma (CP) as a passive source of neutralizing antibodies and immunomodulators is a century-old therapeutic option used for the management of viral diseases. We investigated its effectiveness for the treatment of COVID-19. Design: Open-label, parallel-arm, phase II, multicentre, randomized controlled trial. Setting: Thirty-nine public and private hospitals across India. Participants: Hospitalized, moderately ill confirmed COVID-19 patients (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 ≤ 93% on room air). Intervention: Participants were randomized to either control (best standard of care (BSC)) or intervention (CP + BSC) arm. Two doses of 200 mL CP was transfused 24 hours apart in the intervention arm. Main Outcome Measure: Composite of progression to severe disease (PaO2/FiO2<100) or all-cause mortality at 28 days post-enrolment. Results: Between 22 nd April to 14 th July 2020, 464 participants were enrolled; 235 and 229 in intervention and control arm, respectively. Composite primary outcome was achieved in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77]. Mortality was documented in 34 (14.5%) and 31 (13.5%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: 0.61 to 1.83]. Interpretation: CP was not associated with reduction in mortality or progression to severe COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19.

scholarly journals Potent Plasmablast-Derived Antibodies Elicited by the National Institutes of Health Dengue Vaccine

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Diogo M. Magnani ◽  
Cassia G. T. Silveira ◽  
Michael J. Ricciardi ◽  
Lucas Gonzalez-Nieto ◽  
Núria Pedreño-Lopez ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Somatic Hypermutation ◽  
Neutralizing Antibody ◽  
Therapeutic Interventions ◽  
Phase Iii ◽  
Global Public Health ◽  
Cell Repertoire ◽  
Tetravalent Vaccine ◽  
Dengue Epidemic

ABSTRACT Exposure to dengue virus (DENV) is thought to elicit lifelong immunity, mediated by DENV-neutralizing antibodies (nAbs). However, Abs generated by primary infections confer serotype-specific protection, and immunity against other serotypes develops only after subsequent infections. Accordingly, the induction of these nAb responses acquired after serial DENV infections has been a long-sought-after goal for vaccination. Nonetheless, it is still unclear if tetravalent vaccines can elicit or recall nAbs. In this study, we have characterized the responses from a volunteer who had been previously exposed to DENV and was immunized with the live attenuated tetravalent vaccine Butantan-DV, developed by the NIH and Butantan Institute. Eleven days after vaccination, we observed an ∼70-fold expansion of the plasmablast population. We generated 21 monoclonal Abs (MAbs) from singly sorted plasmablasts. These MAbs were the result of clonal expansions and had significant levels of somatic hypermutation (SHM). Nineteen MAbs (90.5%) neutralized at least one DENV serotype at concentrations of 1 μg/ml or less; 6 of the 21 MAbs neutralized three or more serotypes. Despite the tetravalent composition of the vaccine, we observed a neutralization bias in the induced repertoire: DENV3 was targeted by 18 of the 19 neutralizing MAbs (nMAbs). Furthermore, the P3D05 nMAb neutralized DENV3 with extraordinary potency (concentration to achieve half-maximal neutralization [Neut50] = 0.03 μg/ml). Thus, the Butantan-DV vaccine engendered a mature, antigen-selected B cell repertoire. Our results suggest that preexisting responses elicited by a previous DENV3 infection were recalled by immunization. IMPORTANCE The dengue epidemic presents a global public health challenge that causes widespread economic burden and remains largely unchecked by existing control strategies. Successful control of the dengue epidemic will require effective prophylactic and therapeutic interventions. Several vaccine clinical efficacy trials are approaching completion, and the chances that one or more live attenuated tetravalent vaccines (LATVs) will be introduced worldwide is higher than ever. While it is widely accepted that dengue virus (DENV)-neutralizing antibody (nAb) titers are associated with protection, the Ab repertoire induced by LATVs remain uncharacterized. Here, we describe the isolation of potent (Neut50 < 0.1 μg/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials.

Sign in / Sign up

Export Citation Format

Share Document