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2.
PLoS Pathog ; 15(4): e1007721, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31009499

RESUMO

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Vacinas de Produtos Inativados/imunologia , Viremia/imunologia , Animais , Anticorpos Facilitadores , Dengue/prevenção & controle , Dengue/virologia , Vacinas contra Dengue/administração & dosagem , Modelos Animais de Doenças , Feminino , Macaca mulatta , Masculino , Vacinação , Viremia/virologia
4.
BMC Public Health ; 19(1): 155, 2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30727988

RESUMO

BACKGROUND: The development of a safe and effective vaccine is considered crucial for dengue transmission control since vetor control has been failed; some potential candidates are currently in test, and in this context theoretical studies are necessary to evaluate vaccination strategies such as the age groups that should be vaccinated, the percentage of the population at risk, and the target geographic regions to make dengue control feasible and optimal. METHODS: A partial differential model is used to mimics dengue transmission in human population in order to estimate the optimal vaccination age, using data collected from dengue reported cases in ten cities of Brazil from 2001 to 2014. For this purpose, the basic reproduction number of the disease was minimized assuming a single-dose vaccination strategy, equal vaccine efficacy for all circulating serotypes, and no vaccine failure. Numerical methods were used to assess the optimal vaccination age and its confidence age range. RESULTS: The results reveal complex spatial-temporal patterns associated to the disease transmission, highlighting the heterogeneity in defining the target population for dengue vaccination. However, the values obtained for the optimal age of vaccination, as targeting individuals under 13 years old, are compatible with the ones reported in similar studies in Brazil. The results also show that the optimal age for vaccination in general does not match with the age of the highest number of cases. CONCLUSIONS: The variation of the optimal age for vaccination across the country reflects heterogeneities in dengue spatial-temporal transmission in Brazilian cities, and can be used to define the target population and cities to optimize vaccination strategies in a context of high cost and low quantity of available vaccine.


Assuntos
Vacinas contra Dengue/administração & dosagem , Dengue/prevenção & controle , Dengue/transmissão , Vacinação/métodos , Adolescente , Adulto , Distribuição por Idade , Brasil/epidemiologia , Criança , Pré-Escolar , Cidades , Dengue/epidemiologia , Humanos , Lactente , Recém-Nascido , Pessoa de Meia-Idade , Modelos Teóricos , Análise Espaço-Temporal , Adulto Jovem
5.
Virol Sin ; 34(1): 88-96, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30790202

RESUMO

Dengue fever, caused by dengue viruses (DENVs), is a widespread mosquito-borne zoonotic disease; however, there is no available anti-dengue vaccine for worldwide use. In the current study, a DNA vaccine candidate (pV-D4ME) expressing prM-E protein of DENV serotype 4 (DENV-4) was constructed, and its immunogenicity and protection were evaluated in immunocompetent BALB/c mice. The pV-D4ME candidate vaccine induced effective humoral and cellular immunity of mice against DENV-4 in vivo when administered both at 50 µg and 5 µg through electroporation. Two weeks after receiving three immunizations, both doses of pV-D4ME DNA were shown to confer effective protection against lethal DENV-4 challenge. Notably, at 6 months after the three immunizations, 50 µg, but not 5 µg, of pV-D4ME could provide stable protection (100% survival rate) against DENV-4 lethal challenge without any obvious clinical signs. These results suggest that immunization with 50 µg pV-D4ME through electroporation could confer effective and long-term protection against DENV-4, offering a promising approach for development of a novel DNA vaccine against DENVs.


Assuntos
Antígenos Virais/imunologia , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Eletroporação , Imunização/métodos , Vacinas de DNA/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/genética , Vírus da Dengue , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Sorogrupo , Vacinas de DNA/administração & dosagem , Proteínas Virais/genética , Proteínas Virais/imunologia
6.
PLoS One ; 14(1): e0210041, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30682037

RESUMO

Vaccine efficacy (VE) estimates are crucial for assessing the suitability of dengue vaccine candidates for public health implementation, but efficacy trials are subject to a known bias to estimate VE toward the null if heterogeneous exposure is not accounted for in the analysis of trial data. In light of many well-characterized sources of heterogeneity in dengue virus (DENV) transmission, our goal was to estimate the potential magnitude of this bias in VE estimates for a hypothetical dengue vaccine. To ensure that we realistically modeled heterogeneous exposure, we simulated city-wide DENV transmission and vaccine trial protocols using an agent-based model calibrated with entomological and epidemiological data from long-term field studies in Iquitos, Peru. By simulating a vaccine with a true VE of 0.8 in 1,000 replicate trials each designed to attain 90% power, we found that conventional methods underestimated VE by as much as 21% due to heterogeneous exposure. Accounting for the number of exposures in the vaccine and placebo arms eliminated this bias completely, and the more realistic option of including a frailty term to model exposure as a random effect reduced this bias partially. We also discovered a distinct bias in VE estimates away from the null due to lower detectability of primary DENV infections among seronegative individuals in the vaccinated group. This difference in detectability resulted from our assumption that primary infections in vaccinees who are seronegative at baseline resemble secondary infections, which experience a shorter window of detectable viremia due to a quicker immune response. This resulted in an artefactual finding that VE estimates for the seronegative group were approximately 1% greater than for the seropositive group. Simulation models of vaccine trials that account for these factors can be used to anticipate the extent of bias in field trials and to aid in their interpretation.


Assuntos
Ensaios Clínicos Fase III como Assunto , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Dengue/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Adulto , Viés , Criança , Pré-Escolar , Dengue/tratamento farmacológico , Dengue/virologia , Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/fisiologia , Humanos , Peru , Projetos de Pesquisa , Resultado do Tratamento , Viremia/tratamento farmacológico , Viremia/virologia , Adulto Jovem
7.
Int J Infect Dis ; 84S: S80-S86, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30684747

RESUMO

India is home to nearly a third of the global population at risk of dengue, a viral disease caused by four antigenically and genetically distinct dengue viruses. Clinical illness following dengue virus infection can either be mild and self-limiting dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome, with potentially fatal consequences. A live attenuated vaccine known as Dengvaxia, developed by Sanofi, was licensed in 2015. Following this, long-term follow-up of the Sanofi phase III efficacy trial participants has revealed potential safety concerns. This vaccine, which appears to predispose dengue-naïve recipients to an increased risk of hospitalization in the future, is recommended by the World Health Organization only for adults with a history of prior dengue virus infection. A safe and efficacious dengue vaccine continues to be sought globally. India has joined these efforts in recent years, and is poised to initiate the clinical development of two candidates in the near future, one licensed from abroad and the other developed indigenously. This article provides a glimpse of India's efforts to develop dengue vaccines in the context of the global dengue vaccine development and evaluation landscape and highlights key issues and questions confronting the dengue vaccine community.


Assuntos
Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Animais , Dengue/epidemiologia , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/genética , Vírus da Dengue/genética , Vírus da Dengue/imunologia , Humanos , Vacinas Atenuadas/imunologia
8.
Expert Rev Vaccines ; 18(2): 161-173, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30677305

RESUMO

INTRODUCTION: Dengue fever remains as a health problem worldwide. Although Dengvaxia®, was registered in several countries, the results after the immunization of people suggest an increase of risk in non-immune persons and children younger than 9 years old. No other vaccine is registered so far, thus the development of a safe and effective vaccine continues to be a priority for the WHO and the scientific community. AREAS COVERED: This work reviews the structural and antigenic properties of the capsid protein of Dengue virus, along with results of studies performed to assess the immunogenicity and protective capacity in animals of vaccine candidates based on this protein. EXPERT OPINION: The generation of a memory cellular immune response alone, after vaccination against Dengue virus, could be advantageous, as there would not be risk of increasing viral infectivity through sub-neutralizing antibodies. However, it is improbable to achieving sterilizing immunity. In this scenario, an infection could stablished but without the appearance of the severe disease. The cell-mediated immunity should keep the virus at bay. The capsid protein induces a protective immune response in animals without the induction of virus-binding antibodies. Vaccine candidates based on this protein could be an attractive strategy to induce protection against the severe Dengue disease.


Assuntos
Vacinas contra Dengue/administração & dosagem , Dengue/prevenção & controle , Vacinação/métodos , Animais , Proteínas do Capsídeo/imunologia , Criança , Dengue/epidemiologia , Vírus da Dengue/imunologia , Vírus da Dengue/isolamento & purificação , Saúde Global , Humanos , Imunidade Celular/imunologia
9.
Int J Infect Dis ; 84S: S74-S79, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30641207

RESUMO

INTRODUCTION: Controlled human infection models (CHIM) have been used in vaccine development to up-select and down-select potential vaccine candidates and to provide proof of vaccine efficacy, and have also been used as a basis for licensure of vaccines for cholera and typhoid by regulatory agencies. CHIM IN DENGUE VACCINES DEVELOPMENT: Dengue fever results in ∼400 million infections a year and is of significant health concern especially in India. There are currently no antivirals for the disease and the only licensed vaccine for dengue is not widely used owing to safety concerns. Controlled dengue human challenge models (DHCM) are currently being used to assess the efficacy of vaccines in development for dengue. DENGUE CHIM IN INDIA: Conducting CHIM studies in India especially for evaluation of dengue vaccine candidates will be hugely beneficial as the disease is endemic to India and hence the effect of pre-exposure to the virus on vaccine safety and efficacy can be established. However, to date no CHIM studies have been conducted in India and there is a need to educate ethics committee members, policy makers and the public on the importance of such studies and what they entail.


Assuntos
Bioética , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Desenvolvimento de Medicamentos/ética , Animais , Dengue/economia , Dengue/virologia , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/genética , Desenvolvimento de Medicamentos/economia , Humanos , Modelos Biológicos
10.
Expert Rev Vaccines ; 18(2): 105-117, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30587054

RESUMO

INTRODUCTION: A safe and efficacious vaccine for dengue continues to be an unmet public health need. The recent licensing of a dengue vaccine (Dengvaxia) developed by Sanofi has brought to the fore the safety issue of vaccine-induced infection enhancement. AREAS COVERED: This article focuses on two new yeast-produced tetravalent dengue envelope domain III-displaying virus-like particulate vaccine candidates reported in early 2018 and reviews the rationale underlying their design, and pre-clinical data which suggest that these may offer promising alternate options. EXPERT COMMENTARY: These are the only vaccine candidates so far to have demonstrated the induction of primarily serotype-specific neutralizing antibodies to all dengue virus serotypes in experimental animals. Interestingly, these antibodies lack infection-enhancing potential when evaluated using the AG129 mouse model.


Assuntos
Vacinas contra Dengue/administração & dosagem , Dengue/prevenção & controle , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Animais , Anticorpos Neutralizantes/sangue , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Humanos , Camundongos , Vacinas de Partículas Semelhantes a Vírus/imunologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30501056

RESUMO

Infectious diseases have a huge health and economic burden globally. Vaccination has been found to be a crucial health intervention for diseases. The study aims to compare the drivers of vaccine uptake for influenza and dengue, and to understand the key drivers within each of the diseases in predicting vaccine uptake intentions. Data were collected from 1000 Singaporeans and Singapore permanent residents between the ages of 21 and 70 through face to face surveys. Overall, intention to get vaccinated was low for both diseases. Comparing the means between the knowledge and perceptions regarding influenza and dengue and their vaccine uptake intentions, perceived susceptibility was significantly higher for influenza than dengue; and perceived severity, knowledge of the disease, and benefits of the vaccine were significantly higher for dengue. Looking at the key drivers within the diseases, perceived susceptibility towards the diseases and benefits of the vaccine were positively associated with vaccination uptake intentions for influenza and dengue. Perceived barriers towards the vaccine were negatively associated with vaccine uptake for dengue. Programs conducted for public health promotion should focus on increasing the public's awareness of the susceptibility and seriousness of the diseases, and the benefits of getting vaccinated.


Assuntos
Vacinas contra Dengue/administração & dosagem , Dengue/prevenção & controle , Promoção da Saúde/estatística & dados numéricos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Adulto , Idoso , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Saúde Pública , Singapura , Adulto Jovem
12.
Expert Rev Vaccines ; 17(12): 1123-1133, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30417706

RESUMO

INTRODUCTION: Dengue is a serious global health problem endemic in Brazil. Consequently, our aim was to measure the costs and disease burden of symptomatic dengue infections in Brazil from the perspective of the Brazilian Public Health System (SUS) between 2000 and 2015, using Brazilian public health system databases. Specific age group incidence estimates were used to calculate the disability-adjusted life years (DALYs) to gain a better understanding of the disease burden. Areas covered: SUS spent almost USD159 million and USD10 million to treat dengue and severe dengue, respectively, between 2000 and 2015. This is principally hospitalization costs, with the majority of patients self-treated at home with minor symptoms. The average notification rate for dengue was 273 per 100,000 inhabitants and three per 100,000 for severe dengue, with annual DALYs estimates ranging between 72.35 and 6,824.45 during the 16 years. Expert commentary: The epidemiological and morbidity burden associated with dengue is substantial in Brazil, with costs affected by the fact that most patients self-treat at home with these costs not included in SUS. The Brazilian government urgently needs to proactively evaluate the real costs and clinical benefits of any potential dengue vaccination program by the National Immunization Program to guide future decision-making.


Assuntos
Efeitos Psicossociais da Doença , Vacinas contra Dengue/administração & dosagem , Dengue/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Pré-Escolar , Bases de Dados Factuais , Dengue/economia , Dengue/prevenção & controle , Feminino , Política de Saúde , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Programas de Imunização/organização & administração , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/economia , Programas Nacionais de Saúde/organização & administração , Saúde Pública , Adulto Jovem
14.
Vaccine ; 36(50): 7728-7736, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30377067

RESUMO

A dengue vaccine capable of rapidly eliciting a robust and balanced immunity against the four virus serotypes after only a few immunizations is greatly needed. We describe a new strategy to develop dengue vaccines based on the assembly of virus-like particles (VLPs) utilizing the structural proteins CprME together with a modified complex of the NS2B/NS3 protease, which enhances particle formation and yield. These VLPs are produced in mammalian cells and resemble native dengue virus as demonstrated by negative staining and immunogold labelling electron microscopy (EM). We found that VLPs produced at lower temperature (31 °C) were recognized by conformational monoclonal antibodies (MAbs) 4G2, 3H5 and C10 whereas VLPs produced at higher temperature (37 °C) were not recognized by these MAbs. To investigate the significance of these conformational discrepancies in vaccine performance, we tested the immunogenicity of VLP vaccines produced at 31 °C or 37 °C. Mice immunized with the VLP vaccine produced at 31 °C (VLP-31 °C) elicited the highest titer of neutralizing antibodies when compared to those elicited by equivalent doses of the vaccine produced at 37 °C (VLP-37 °C), inactivated dengue virus vaccine or to the titer of a human anti-dengue-2 convalescence serum reference. Our results demonstrate that the conformation of the E protein displayed on the VLP vaccine plays a critical role in the induction of highly neutralizing antibodies. These findings will guide development of a tetravalent vaccine capable of eliciting a robust and balanced neutralizing response against the four-dengue serotypes regardless of background immunity.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Tecnologia Farmacêutica/métodos , Temperatura Ambiente , Vacinas de Partículas Semelhantes a Vírus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/administração & dosagem , Antígenos Virais/imunologia , Dengue/prevenção & controle , Vacinas contra Dengue/administração & dosagem , Camundongos Endogâmicos BALB C , Conformação Proteica , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Proteínas do Envelope Viral/administração & dosagem , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia
15.
BMC Med Res Methodol ; 18(1): 134, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442099

RESUMO

BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue.


Assuntos
Ensaios Clínicos como Assunto , Vacinas contra Dengue/uso terapêutico , Dengue/prevenção & controle , Determinação de Ponto Final/métodos , Técnica Delfos , Dengue/terapia , Vacinas contra Dengue/administração & dosagem , Determinação de Ponto Final/normas , Hospitalização/estatística & dados numéricos , Humanos , /normas , Reprodutibilidade dos Testes
16.
17.
Microb Cell Fact ; 17(1): 146, 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30217208

RESUMO

BACKGROUND: Dengue is a rapidly spreading mosquito borne tropical viral disease affecting hundreds of millions of people across the globe annually. The dengue virus (DENV) includes four genetically distinct serotypes that cause serious life-threatening infections, including dengue hemorrhagic fever/dengue shock syndrome. Dengue vaccine development is complicated by the possibility of vaccine-enhanced severe dengue disease due to antibody-dependent enhancement by pre-existing cross-reactivity, as well as homotypic antibodies. Thus, the development of an efficacious dengue vaccine conferring simultaneous and durable immunity to each of the four DENV serotypes has not yet been developed despite years of research. For mass immunization in deeply affected resource-limited countries, oral vaccination is considered more beneficial than conventional approaches. Therefore, in a continuing effort towards designing economical and potent vaccine candidates, the current study applied yeast surface display technology to develop an oral dengue vaccine candidate using whole recombinant yeast cells displaying the recombinant fusion protein of M cell targeting ligand Co1 fused to the synthetic consensus dengue envelope domain III (scEDIII). Female Balb/c mice were orally fed with recombinant yeast cells and immunogenicity in terms of systemic and mucosal immune responses was monitored. RESULTS: Immunofluorescence microscopy with dengue specific antibody and fluorescein isothiocyanate-conjugated anti-mouse IgG antibody clearly showed that recombinant protein Co1-scEDIII-AGA was localized on the cell surface of the respective clones in comparison with scEDIII-Co1 and Mock cells with no fluorescence. Oral dosage applications of surface displayed Co1-scEDIII-AGA stimulated a systemic humoral immune response in the form of dengue-specific serum IgG, as well as a mucosal immune response in the form of secretory immunoglobulin A (sIgA). Antigen-specific B cell responses in isolated lymphoid cells from the spleen and Peyer's patches further supported an elevated mucosal immune response. In addition, surface displayed Co1-scEDIII-AGA feeding elicited strong immune responses in comparison with scEDIII-Co1 and Mock following intraperitoneal booster with purified scEDIII antigen. CONCLUSIONS: Surface displayed preparations of Co1-scEDIII-AGA induced strong immunogenicity compared with non-displayed scEDIII-Co1. Prior studies have supported the neutralization potential of scEDIII constructs against all four serotypes. Thus, the oral administration of genetically engineered yeast whole cells displaying biologically active Co1-scEDIII fusion protein without any further processing shows prospective as a potent oral vaccine candidate against dengue viral infection.


Assuntos
Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/imunologia , Saccharomyces cerevisiae/genética , Animais , Técnicas de Visualização da Superfície Celular , Ensaio de Imunoadsorção Enzimática , Feminino , Imunidade Humoral , Imunidade nas Mucosas , Camundongos Endogâmicos BALB C , Saccharomyces cerevisiae/metabolismo , Proteínas Virais/análise , Proteínas Virais/genética , Proteínas Virais/imunologia
18.
Math Biosci ; 305: 102-121, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30218686

RESUMO

This paper presents a deterministic model for dengue virus transmission. The model is parameterized using data from the 2017 dengue outbreak in Pakistan. We estimated the basic reproduction number (R0) without any interventions for the 2017 dengue outbreak in Peshawar district of Pakistan as R0≈2.64, the distribution of the reproduction number lies in the range R0∈[1.21,5.24] (with a mean R0≈2.64). Optimal control theory is then applied to investigate the optimal strategy for curtailing the spread of the disease using two time-dependent control variables determined from sensitivity analysis. These control variables are insecticide use and vaccination. The results show that the two controls avert the same number of infections in the district regardless of the weights on the costs this is due to the reciprocal relationship between the cost of insecticide use and vaccination. A strong reciprocal relationship exists between the use of insecticide and vaccination; as the cost of insecticide increases the use of vaccination increases. The use of insecticide on the other hand slightly increases when vaccination level decreases due to increase in cost.


Assuntos
Dengue/prevenção & controle , Dengue/transmissão , Modelos Biológicos , Aedes/virologia , Algoritmos , Animais , Número Básico de Reprodução , Simulação por Computador , Dengue/epidemiologia , Vacinas contra Dengue/administração & dosagem , Surtos de Doenças/prevenção & controle , Feminino , Humanos , Mordeduras e Picadas de Insetos/virologia , Inseticidas/administração & dosagem , Conceitos Matemáticos , Mosquitos Vetores/virologia , Paquistão/epidemiologia , Vacinação
19.
PLoS Negl Trop Dis ; 12(9): e0006793, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30248097

RESUMO

Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic shock syndrome. Dengue vaccine development is challenging because of the need to induce protection against four antigenically distinct DENV serotypes. Recent studies indicate that tetravalent DENV vaccines must induce balanced, serotype-specific neutralizing antibodies to achieve durable protective immunity against all 4 serotypes. With the leading live attenuated tetravalent DENV vaccines, it has been difficult to achieve balanced and type-specific responses to each serotype, most likely because of unbalanced replication of vaccine viral strains. Here we evaluate a tetravalent DENV protein subunit vaccine, based on recombinant envelope protein (rE) adsorbed to the surface of poly (lactic-co-glycolic acid) (PLGA) nanoparticles for immunogenicity in mice. In monovalent and tetravalent formulations, we show that particulate rE induced higher neutralizing antibody titers compared to the soluble rE antigen alone. Importantly, we show the trend that tetravalent rE adsorbed to nanoparticles stimulated a more balanced serotype specific antibody response to each DENV serotype compared to soluble antigens. Our results demonstrate that tetravalent DENV subunit vaccines displayed on nanoparticles have the potential to overcome unbalanced immunity observed for leading live-attenuated vaccine candidates.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Nanopartículas/administração & dosagem , Proteínas Estruturais Virais/imunologia , Animais , Vacinas contra Dengue/administração & dosagem , Feminino , Camundongos Endogâmicos BALB C , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Vacinas de Subunidades/administração & dosagem , Vacinas de Subunidades/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
20.
Proc Natl Acad Sci U S A ; 115(36): E8378-E8387, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30127007

RESUMO

Two phase 3 placebo-controlled trials of the CYD-TDV vaccine, evaluated in children aged 2-14 y (CYD14) and 9-16 y (CYD15), demonstrated vaccine efficacy (VE) of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue (VCD). Sieve analyses were conducted to evaluate whether and how VE varied with amino acid sequence features of dengue viruses (DENVs). DENV premembrane/envelope amino acid sequences from VCD endpoint cases were aligned with the vaccine insert sequences, and extensions of the proportional hazards model were applied to assess variation in VE with amino acid mismatch proportion distances from vaccine strains, individual amino acid residues, and phylogenetic genotypes. In CYD14, VE against VCD of any serotype (DENV-Any) decreased significantly with increasing amino acid distance from the vaccine, whereas in CYD15, VE against DENV-Any was distance-invariant. Restricting to the common age range and amino acid distance range between the trials and accounting for differential VE by serotype, however, showed no evidence of VE variation with distance in either trial. In serotype-specific analyses, VE against DENV4 decreased significantly with increasing amino acid distance from the DENV4 vaccine insert and was significantly greater against residue-matched DENV4 at eight signature positions. These effects were restricted to 2- to 8-y-olds, potentially because greater seropositivity of older children at baseline might facilitate a broader protective immune response. The relevance of an antigenic match between vaccine strains and circulating DENVs was also supported by greater estimated VE against serotypes and genotypes for which the circulating DENVs had shorter amino acid sequence distances from the vaccine.


Assuntos
Vacinas contra Dengue/administração & dosagem , Vírus da Dengue/genética , Dengue/prevenção & controle , Variação Genética , Genótipo , Fatores Etários , Criança , Pré-Escolar , Dengue/genética , Dengue/imunologia , Vacinas contra Dengue/genética , Vacinas contra Dengue/imunologia , Vírus da Dengue/imunologia , Feminino , Humanos , Masculino
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