scholarly journals Tracking the polyclonal neutralizing antibody response to a dengue virus serotype 1 type-specific epitope across two populations in Asia and the Americas

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniela V. Andrade ◽  
Colin Warnes ◽  
Ellen Young ◽  
Leah C. Katzelnick ◽  
Angel Balmaseda ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Sri Lankan ◽  
Human Monoclonal Antibodies ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Dengue Virus Serotypes ◽  
Kinetics Of ◽  
Two Populations

Abstract The four dengue virus serotypes (DENV1-4) cause major public health problems worldwide. Highly neutralizing type-specific human monoclonal antibodies (hmAbs) target conformation-dependent epitopes on the DENV envelope protein, including 1F4, a DENV1 type-specific hmAb. Using a recombinant DENV2 virus displaying the DENV1 1F4 epitope (rDENV2/1), we measured the proportion and kinetics of DENV1 neutralizing antibodies targeting the 1F4 epitope in individuals living in Asia and the Americas where different DENV1 genotypes were circulating. Samples from 20 individuals were analyzed 3 and 18 months post-primary DENV1 infection, alongside samples from 4 individuals collected annually for four years post-primary DENV1 infection, from two studies in Nicaragua. We also analyzed convalescent post-primary DENV1 plasma samples from Sri Lankan individuals. We found that neutralizing antibodies recognizing the 1F4 epitope vary in prevalence across both populations and were detected from 20 days to four years post-infection. Additionally, both populations displayed substantial variability, with a range of high to low proportions of DENV1 type-specific neutralizing antibodies recognizing the 1F4 epitope seen across individuals. Thus, the 1F4 epitope is a major but not exclusive target of type-specific neutralizing antibodies post-primary infection with different DENV1 genotypes in Asia and Latin America, and additional epitopes likely contribute to type-specific neutralization of DENV1.

scholarly journals Rapid Subtyping of Dengue Virus Serotypes 1 and 4 by Restriction Site-Specific PCR

2000 ◽  
Vol 38 (3) ◽  
pp. 1286-1289 ◽  
Author(s):  
Marize P. Miagostovich ◽  
Flavia B. dos Santos ◽  
C. Milena Gutiérrez ◽  
Lee W. Riley ◽  
Eva Harris
Keyword(s):  
Sequence Analysis ◽  
Dengue Virus ◽  
Restriction Site ◽  
Epidemiological Studies ◽  
Site Specific ◽  
Specific Pcr ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Dengue Virus Serotypes ◽  
Dengue Virus Serotype 1

We previously reported a simple subtyping method, restriction site-specific PCR (RSS-PCR), for dengue virus serotypes 2 and 3; here we describe its application for subtyping dengue virus serotypes 1 and 4. Three major RSS-PCR types were observed for dengue virus serotype 1 and two types were observed for dengue virus serotype 4, in agreement with previous strain classifications based on sequence analysis. Because of its simplicity, this method is amenable to rapid subtyping and application to epidemiological studies of dengue in countries where dengue is endemic.

A dengue virus serotype-1 DNA vaccine induces virus neutralizing antibodies and provides protection from viral challenge in Aotus monkeys

Vaccine ◽  
2000 ◽  
Vol 18 (27) ◽  
pp. 3166-3173 ◽  
Author(s):  
T.J Kochel ◽  
K Raviprakash ◽  
C.G Hayes ◽  
D.M Watts ◽  
K.L Russell ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Viral Challenge ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Dengue Virus Serotype 1

scholarly journals Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

2021 ◽  
Vol 15 (3) ◽  
pp. e0009258
Author(s):  
Laura J. White ◽  
Ellen F. Young ◽  
Mark J. Stoops ◽  
Sandra R. Henein ◽  
Elizabeth C. Adams ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Severe Disease ◽  
Dengue Vaccine ◽  
Unique Type ◽  
Tropical Regions ◽  
Efficacy Trials ◽  
Virus Serotype ◽  
Dengue Virus Serotypes

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.

scholarly journals Mapping the Human Memory B Cell and Serum Neutralizing Antibody Responses to Dengue Virus Serotype 4 Infection and Vaccination

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Usha K. Nivarthi ◽  
Nurgun Kose ◽  
Gopal Sapparapu ◽  
Douglas Widman ◽  
Emily Gallichotte ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Dengue Fever ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Antibody Responses ◽  
Human Antibodies ◽  
E Protein ◽  
Virus Serotype

ABSTRACT The four dengue virus (DENV) serotypes are mosquito-borne flaviviruses responsible for dengue fever and dengue hemorrhagic fever. People exposed to DENV develop antibodies (Abs) that strongly neutralize the serotype responsible for infection. Historically, infection with DENV serotype 4 (DENV4) has been less common and less studied than infections with the other three serotypes. However, DENV4 has been responsible for recent large and sustained epidemics in Asia and Latin America. The neutralizing antibody responses and the epitopes targeted against DENV4 have not been characterized in human infection. In this study, we mapped and characterized epitopes on DENV4 recognized by neutralizing antibodies in people previously exposed to DENV4 infections or to a live attenuated DENV4 vaccine. To study the fine specificity of DENV4 neutralizing human antibodies, B cells from two people exposed to DENV4 were immortalized and screened to identify DENV-specific clones. Two human monoclonal antibodies (MAbs) that neutralized DENV4 were isolated, and their epitopes were finely mapped using recombinant viruses and alanine scan mutation array techniques. Both antibodies bound to quaternary structure epitopes near the hinge region between envelope protein domain I (EDI) and EDII. In parallel, to characterize the serum neutralizing antibody responses, convalescence-phase serum samples from people previously exposed to primary DENV4 natural infections or a monovalent DENV4 vaccine were analyzed. Natural infection and vaccination also induced serum-neutralizing antibodies that targeted similar epitope domains at the EDI/II hinge region. These studies defined a target of neutralizing antigenic site on DENV4 targeted by human antibodies following natural infection or vaccination. IMPORTANCE The four serotypes of dengue virus are the causative agents of dengue fever and dengue hemorrhagic fever. People exposed to primary DENV infections develop long-term neutralizing antibody responses, but these principally recognize only the infecting serotype. An effective vaccine against dengue should elicit long-lasting protective antibody responses to all four serotypes simultaneously. We and others have defined antigenic sites on the envelope (E) protein of viruses of dengue virus serotypes 1, 2, and 3 targeted by human neutralizing antibodies. The epitopes on DENV4 E protein targeted by the human neutralizing antibodies and the mechanisms of serotype 4 neutralization are poorly understood. Here, we report the properties of human antibodies that neutralize dengue virus serotype 4. People exposed to serotype 4 infections or a live attenuated serotype 4 vaccine developed neutralizing antibodies that bound to similar sites on the viral E protein. These studies have provided a foundation for developing and evaluating DENV4 vaccines.

scholarly journals The Chimeric Protein Domain III-Capsid of Dengue Virus Serotype 2 (DEN-2) Successfully Boosts Neutralizing Antibodies Generated in Monkeys upon Infection with DEN-2

2011 ◽  
Vol 18 (3) ◽  
pp. 455-459 ◽  
Author(s):  
Iris Valdés ◽  
Lázaro Gil ◽  
Yaremis Romero ◽  
Jorge Castro ◽  
Pedro Puente ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Chimeric Protein ◽  
Neutralizing Antibody ◽  
Protein Domain ◽  
Homologous Virus ◽  
Virus Serotype ◽  
Attenuated Virus ◽  
Domain Iii ◽  
Dengue Virus Serotype 2

ABSTRACTUse of a heterologous prime-boost strategy based on a combination of nonreplicative immunogens and candidate attenuated virus vaccines against dengue virus in the same schedule is an attractive approach. These combinations may result in a condensed immunization regime for humans, thus reducing the number of doses with attenuated virus and the time spacing. The present work deals with the evaluation of the heterologous prime-boost strategy combining a novel chimeric protein (domain III-capsid) of dengue virus serotype 2 (DEN-2) and the infective homologous virus in the same immunization schedule in monkeys. Primed monkeys received one dose of infective DEN-2 and were then vaccinated with the recombinant protein. We found that animals developed a neutralizing antibody response after the infective dose and were notably boosted with a second dose of the chimeric protein 3 months later. The neutralizing antibodies induced were long lasting, and animals also showed the ability to induce a specific cellular response 6 months after the booster dose. As a conclusion, we can state that the domain III region, when it is properly presented as a fusion protein to the immune system, is able to recall the neutralizing antibody response elicited following homologous virus infection in monkeys. Further prime-boost approaches can be performed in a condensed regime combining the chimeric domain III-capsid protein and candidate live attenuated vaccines against DEN-2.

scholarly journals A Dengue Virus Serotype 1 mRNA-LNP Vaccine Elicits Protective Immune Responses

2021 ◽  
Author(s):  
Clayton J. Wollner ◽  
Michelle Richner ◽  
Mariah A. Hassert ◽  
Amelia K. Pinto ◽  
James D. Brien ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dengue Virus ◽  
Viral Infection ◽  
Neutralizing Antibody ◽  
Viral Disease ◽  
Structural Proteins ◽  
Severe Dengue ◽  
Antibody Dependent Enhancement ◽  
Virus Serotype ◽  
Serotype 1

Dengue virus (DENV) is the most common vector-borne viral disease with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly-neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding for the membrane and envelope structural proteins from DENV serotype 1 encapsulated into lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection with high levels of neutralizing antibody titers and antiviral CD4+ and CD8+ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine, or a vaccine with mutations in the immunodominant fusion-loop epitope, elicited equivalent humoral and cell mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype specific immunity with minimal serum cross-reactivity and reduced ADE compared to a live DENV1 viral infection. IMPORTANCE With 400 million worldwide infections each year, dengue is the most common vector-born viral disease. 40% of the world's population is at risk with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing sub optimally, the need for an effective dengue vaccine is urgent. Here we develop and characterize a novel mRNA vaccine encoding for the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement. Importantly our vaccine only induced serotype specific immune responses and did not induce ADE.

scholarly journals Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single Amino Acid Mutation That Modulates Virus Breathing

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Kimberly A. Dowd ◽  
Christina R. DeMaso ◽  
Theodore C. Pierson
Keyword(s):  
Amino Acid ◽  
Dengue Virus ◽  
Vaccine Development ◽  
Antibody Binding ◽  
Single Amino Acid ◽  
Genotypic Differences ◽  
Conformational Ensembles ◽  
Single Amino Acid Residue ◽  
Virus Serotype ◽  
Serotype 1

ABSTRACTFlaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of dengue virus serotype 1 (DENV1). Prior studies indicated that an observed ~200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13 amino acid differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a lysine or arginine at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this amino acid dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by DENV. That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development.IMPORTANCEThe global burden of dengue virus (DENV) is growing, with recent estimates of ~390 million human infections each year. Antibodies play a crucial role in protection from DENV infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single amino acid residue in the envelope protein of DENV serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of DENV-reactive antibodies.

scholarly journals Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes

2018 ◽  
Vol 14 (2) ◽  
pp. e1006934 ◽  
Author(s):  
Emily N. Gallichotte ◽  
Thomas J. Baric ◽  
Boyd L. Yount ◽  
Douglas G. Widman ◽  
Anna Durbin ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Virus Serotype ◽  
Dengue Virus Serotype 2

Force of infection of dengue serotypes in a population-based study in the northeast of Brazil

2012 ◽  
Vol 141 (5) ◽  
pp. 1080-1088 ◽  
Author(s):  
P. M. S. CASTANHA ◽  
M. T. CORDEIRO ◽  
C. M. T. MARTELLI ◽  
W. V. SOUZA ◽  
E. T. A. MARQUES ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Dengue Infection ◽  
Population Based ◽  
Northeastern Brazil ◽  
Population Based Study ◽  
Force Of Infection ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Frequent Infection ◽  
Dengue Virus Serotype 1

SUMMARYThis study investigated anti-dengue serotype-specific neutralizing antibodies in a random sample of dengue IgG-positive individuals identified in a survey performed in a hyperendemic setting in northeastern Brazil in 2005. Of 323 individuals, 174 (53·8%) had antibodies to dengue virus serotype 1 (DENV-1), 104 (32·2%) to DENV-2 and 301 (93·2%) to DENV-3. Monotypic infections by DENV-3 were the most frequent infection (35·6%). Of 109 individuals aged <15 years, 61·5% presented multitypic infections. The force of infection estimated by a catalytic model was 0·9%, 0·4% and 2·5% person-years for DENV-1, DENV-2 and DENV-3, respectively. By the age of 5 years, about 70%, 30% and 40% of participants were immune to DENV-3, DENV-2 and DENV-1, respectively. The data suggest that infection with DENV-1, -2 and -3 is intense at early ages, demonstrating the need for research efforts to investigate dengue infection in representative population samples of Brazilian children during early infancy.

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