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

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 ?g/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 ?g/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 ?g/ml) nAbs from a DENV-seropositive volunteer immunized with the tetravalent vaccine Butantan-DV, which is currently in phase III trials.

SUBMITTER: Magnani DM

PROVIDER: S-EPMC5660501 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Magnani Diogo M DM Silveira Cassia G T CGT Ricciardi Michael J MJ Gonzalez-Nieto Lucas L Pedreño-Lopez Núria N Bailey Varian K VK Gutman Martin J MJ Maxwell Helen S HS Domingues Aline A Costa Priscilla R PR Ferrari Lilian L Goulart Raphaella R Martins Mauricio A MA Martinez-Navio José M JM Fuchs Sebastian P SP Kalil Jorge J Timenetsky Maria do Carmo MDC Wrammert Jens J Whitehead Stephen S SS Burton Dennis R DR Desrosiers Ronald C RC Kallas Esper G EG Watkins David I DI

Journal of virology 20171027 22

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 ...[more]

PMID: 28878078

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Project description:The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (domain I [DI], DII, and DIII). Recent studies reported that human monoclonal antibodies (MAbs) recognizing DIII, the D1/DII hinge, the E-dimer epitope, or a quaternary epitope involving DI/DII/DIII are more potently neutralizing than those recognizing the fusion loop (FL) of DII. Due to inefficient cleavage of the premembrane protein, DENV suspensions consist of a mixture of mature, immature, and partially immature particles. We investigated the neutralization and binding of 22 human MAbs to DENV serotype 1 (DENV1) virions with differential maturation status. Compared with FL MAbs, DIII, DI/DII hinge, and E-dimer epitope MAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such MAbs. FL-specific MAbs required 57 to 87% occupancy on mature particles to achieve half-maximal neutralization (NT50), whereas the potently neutralizing MAbs achieved NT50 states at 20 to 38% occupancy. Analysis of the MAb repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing MAbs. Taken together, these findings suggest that the use of homogeneous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than the use of immature or mixed particles.IMPORTANCE With an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine Dengvaxia was licensed; however, its low efficacy among dengue-naive individuals and increased risk of causing severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions contain mature, immature, and partially immature particles. We investigated the binding of 22 human monoclonal antibodies (MAbs) to the DENV envelope protein on particles with different maturation states. Potently neutralizing MAbs had higher relative maximum binding and avidity to mature particles than weakly neutralizing MAbs. This was supported by analysis of MAb repertoires and polyclonal sera from patients with primary DENV infection. Together, these findings suggest that mature particles may be the optimal form of presentation of the envelope protein to induce more potent neutralizing antibodies against DENV.

Project description:BackgroundReadmissions are a common problem in cardiac surgery. The goal of this study was to examine the frequency, timing, and associated risk factors for readmission after cardiac operations.MethodsA 10-center cohort study prospectively enrolled 5,158 adult cardiac surgical patients (5,059 included in analysis) to assess risk factors for infection after cardiac operations. Data were also collected on all-cause readmissions occurring within 65 days after the operation. Major outcomes included the readmission rate stratified by procedure type, cause of readmission, length of readmission stay, and discharge disposition after readmission. Multivariable Cox regression was used to determine risk factors for time to first readmission.ResultsThe overall rate of readmission was 18.7% (number of readmissions, 945). When stratified by the most common procedure type, readmission rates were isolated coronary artery bypass grafting, 14.9% (n = 248); isolated valve, 18.3% (n = 337); and coronary artery bypass grafting plus valve, 25.0% (n = 169). The three most common causes of first readmission within 30 days were infection (17.1% [n = 115]), arrhythmia (17.1% [n = 115]), and volume overload (13.5% [n = 91]). More first readmissions occurred within 30 days (80.6% [n = 672]) than after 30 days (19.4% [n = 162]), and 50% of patients were readmitted within 22 days from the index operation. The median length of stay during the first readmission was 5 days. Discharge in 15.8% of readmitted patients (n = 128) was to a location other than home. Baseline patient characteristics associated with readmission included female gender, diabetes mellitus on medication, chronic obstructive pulmonary disease, elevated creatinine, lower hemoglobin, and longer operation time. More complex surgical procedures were associated with an increased risk of readmission compared with the coronary artery bypass grafting group.ConclusionsNearly 1 of 5 patients who undergo cardiac operations require readmission, an outcome with significant health and economic implications. Management practices to avert in-hospital infections, reduce postoperative arrhythmias, and avoid volume overload offer important targets for quality improvement.

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

Publications

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

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