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1.
Mem Inst Oswaldo Cruz ; 114: e190187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31826129

RESUMO

BACKGROUND: The Yellow Fever (YF) vaccine is produced by the inoculation of embryonated chicken eggs with YF17DD virus on the ninth day of development. Full embryos are collected on the twelfth day of development for vaccine formulation. Skeletal muscle tissue is the main site where biosynthesis of viral particles occurs. OBJECTIVES: This study aimed to analyse the experimental infection of skeletal muscle cells of chicken embryos by the 17DD Yellow Fever virus (YFV) in vivo and in vitro. METHODS: Chicken embryos infected with YF17DD virus were analysed by immunofluorescence using confocal and super-resolution microscopes. Primary cultures of skeletal muscle cells of non-infected chicken embryos were evaluated for susceptibility and permissiveness to YF17DD virus using different protocols. This evaluation was performed based on morphological, viral titration, molecular biology, and colorimetric techniques. FINDINGS: The present work phenotypically characterises embryonic chicken skeletal muscle cells as myogenic precursors expressing the Pax7 transcription factor in some cases. We demonstrated that these cells are susceptible to in vitro infection at different multiplicities of infection (MOIs), reproducing the same infection pattern observed in vivo. Furthermore, myogenic precursors and myoblasts are preferred infection targets, but establishment of infection does not depend on the presence of these cells. The peak of viral production occurred at 48 hpi, with decay occurring 72 hpi, when the cytopathic effect can be observed. MAIN CONCLUSIONS: In conclusion, the primary culture of chicken skeletal muscle cells is a good model for studying muscle cells infected with YF17DD virus. This culture system displays satisfactory emulation of the in vitro phenomenon observed, contributing to our understanding of virus infection dynamics and leading to the development of alternative methods of vaccine production.


Assuntos
Músculo Esquelético/virologia , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Animais , Células Cultivadas , Embrião de Galinha , Imunofluorescência , Cultura de Vírus , Replicação Viral/fisiologia , Vacina contra Febre Amarela/biossíntese , Vírus da Febre Amarela/crescimento & desenvolvimento
3.
PLoS Negl Trop Dis ; 13(8): e0007299, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31412040

RESUMO

BACKGROUND: To be transmitted to vertebrate hosts via the saliva of their vectors, arthropod-borne viruses have to cross several barriers in the mosquito body, including the midgut infection and escape barriers. Yellow fever virus (YFV) belongs to the genus Flavivirus, which includes human viruses transmitted by Aedes mosquitoes, such as dengue and Zika viruses. The live-attenuated YFV-17D vaccine has been used safely and efficiently on a large scale since the end of World War II. Early studies have shown, using viral titration from salivary glands of infected mosquitoes, that YFV-17D can infect Aedes aegypti midgut, but does not disseminate to other tissues. METHODOLOGY/PRINCIPAL FINDINGS: Here, we re-visited this issue using a panel of techniques, such as RT-qPCR, Western blot, immunofluorescence and titration assays. We showed that YFV-17D replication was not efficient in Aedes aegypti midgut, as compared to the clinical isolate YFV-Dakar. Viruses that replicated in the midgut failed to disseminate to secondary organs. When injected into the thorax of mosquitoes, viruses succeeded in replicating into midgut-associated tissues, suggesting that, during natural infection, the block for YFV-17D replication occurs at the basal membrane of the midgut. CONCLUSIONS/SIGNIFICANCE: The two barriers associated with Ae. aegypti midgut prevent YFV-17D replication. Our study contributes to our basic understanding of vector-pathogen interactions and may also aid in the development of non-transmissible live virus vaccines.


Assuntos
Aedes/virologia , Trato Gastrointestinal/virologia , Replicação Viral/efeitos dos fármacos , Vacina contra Febre Amarela/farmacologia , Vírus da Febre Amarela/efeitos dos fármacos , Vírus da Febre Amarela/crescimento & desenvolvimento , Animais , Linhagem Celular , Trato Gastrointestinal/fisiologia , Interações Hospedeiro-Patógeno/fisiologia , Mosquitos Vetores , Glândulas Salivares , Vacinas Atenuadas , Carga Viral , Vírus da Febre Amarela/genética
4.
PLoS Negl Trop Dis ; 13(8): e0007661, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425507

RESUMO

BACKGROUND: French Guiana, a French overseas department located in South America between Brazil and Surinam, is the only European territory geographically located in the Amazonian forest complex and is considered endemic for yellow fever (YF). In the context of the emergent threat of YF in Latin America, we conducted a large household cross-sectional survey from June to October 2017 to estimate vaccination coverage in the population and to determine associations with sociodemographic and geographical characteristics. METHODOLOGY/PRINCIPAL FINDINGS: In total, 1,415 households and 2,697 individuals were included from the 22 municipalities of French Guiana. YF vaccination coverage was estimated at 95.0% (95% CI: 93.4-96.2) in the entire territory but was spatially heterogeneous, with the lowest levels estimated in the western part of the territory along the Surinamese cross-border region, particularly in children under 16 years who were not enrolled in school, immigrant adults and disadvantaged populations with low socioeconomic indexes. CONCLUSIONS/SIGNIFICANCE: Despite the good vaccination coverage against YF in the general population of French Guiana resulting from the compulsory nature of YF vaccination for residents and travelers, there is an urgent need to improve vaccination coverage in vulnerable populations living in the northwestern part of the territory to limit the risk of transmission in the context of the emerging YF threat in South America. Despite the relative rarity of YF and the significant number of infectious and tropical diseases in French Guiana, clinicians should adopt a high index of suspicion for YF, particularly in vulnerable and at-risk populations.


Assuntos
Transmissão de Doença Infecciosa/prevenção & controle , Cobertura Vacinal/estatística & dados numéricos , Vacina contra Febre Amarela/administração & dosagem , Febre Amarela/epidemiologia , Febre Amarela/prevenção & controle , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Demografia , Características da Família , Feminino , Guiana Francesa/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Adulto Jovem
5.
J Korean Med Sci ; 34(33): e217, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31436051

RESUMO

BACKGROUND: Pre-travel medical consultation is essential to reduce health impairment during travel. Yellow fever vaccination (YFV) is mandatory to enter some endemic countries. In this study, we evaluated the factors that affect compliance with appropriate prevention of infectious diseases in travelers who visited clinic for YFV. METHODS: For this retrospective study, chart reviews for 658 patients who visited a travel clinic for YFV before travel were conducted. The period of this study was from January 2016 to September 2018. The associations between appropriate vaccination and factors such as travel duration, destination, time of visiting clinic before departure, and purpose of travel were analyzed. RESULTS: Among 658 patients who got YFV during the study period, 344 patients (52.3%) received additional vaccination or malaria prophylaxis following a physician's recommendation. Travelers who visited the clinic more than 21 days before departure were more compliant than those who visited 14 days or fewer before departure (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.23-2.93; P = 0.004). Travelers visiting Africa were more compliant than were those traveling to South and Central America (OR, 1.97; 95% CI, 1.34-2.90; P = 0.001). Travelers in age groups of 40-49 years and over 70 years were less compliant than the 18-29 years old population (OR, 0.51; 95% CI, 0.28-0.93; P = 0.027 and OR, 0.19; 95% CI, 0.04-0.84; P = 0.03, respectively). Also, those who traveled for tour or to visit friends or relatives were more compliant than those who departed for business (OR, 0.77; 95% CI, 1.03-3.56; P = 0.04). CONCLUSION: For appropriate vaccination, pre-travel consultation at least 3 weeks before departure is crucial. Travelers should be aware of required vaccination and malaria prophylaxis before visiting South and Central America and Asia. Plans to enhance compliance of the elderly and business travelers should be contrived.


Assuntos
Cooperação do Paciente , Viagem/psicologia , Febre Amarela/prevenção & controle , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Vacinação , Febre Amarela/imunologia , Vacina contra Febre Amarela/imunologia , Adulto Jovem
7.
Emerg Infect Dis ; 25(8): 1511-1521, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31298654

RESUMO

We evaluated the duration of neutralizing antibodies and the status of 17DD vaccine-specific T- and B-cell memory following primary and revaccination regimens for yellow fever (YF) in Brazil. We observed progressive decline of plaque-reduction neutralization test (PRNT) seropositivity and of the levels of effector memory CD4+ and CD8+ T cells, as well as interferon-γ+CD8+ T cells, 10 years after primary vaccination. Revaccination restored PRNT seropositivity as well as the levels of effector memory CD4+, CD8+, and interferon-γ+CD8+ T cells. Moreover, secondary or multiple vaccinations guarantee long-term persistence of PRNT positivity and cell-mediated memory 10 years after booster vaccination. These findings support the relevance of booster doses to heighten the 17DD-YF-specific immune response to guarantee the long-term persistence of memory components. Secondary or multiple vaccinations improved the correlates of protection triggered by 17DD-YF primary vaccination, indicating that booster regimens are needed to achieve efficient immunity in areas with high risk for virus transmission.


Assuntos
Imunidade , Imunização Secundária , Vacina contra Febre Amarela/imunologia , Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Brasil/epidemiologia , Vírus da Dengue/imunologia , Feminino , Humanos , Imunidade Celular , Imunoglobulina G/imunologia , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Vigilância em Saúde Pública , Vacina contra Febre Amarela/administração & dosagem , Adulto Jovem
8.
Eur J Pharm Biopharm ; 142: 334-343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306751

RESUMO

The stability of live-attenuated viruses is very challenging due to thermal sensitivity; therefore, solid form is usually required (often freeze-dried products). Micropellet technology is a lyophilization technology that has the potential to provide greater flexibility in the presentation of a given vaccine particularly in multi-dose format or in combination of different vaccines. As a novel vaccine alternative process, this spray freeze-dried (SFD) micropellet technology was evaluated using as a model a yellow fever virus produced in Vero cells (vYF). Screening of excipients was performed in order to optimize physico-chemical properties of the micropellets. Sugar/polymer-based formulations induced high glass transition temperature (Tg), adequate breaking force and attrition resistance of the SFD micropellets. These mechanical parameters and their stability are of considerable importance for the storage, the transport but also the filling process of the SFD micropellets. By adding excipients required to best preserve virus infectivity, an optimal sugar/polymer-based formulation was selected to build micropellets containing vYF. Monodisperse and dried micropellets with a diameter of about 530 µm were obtained, exhibiting similar potency to conventional freeze-dried product in terms of vYF infectious titer when both solid forms were kept under refrigerated conditions (2-8 °C). Comparable kinetics of degradation were observed for vYF formulated in micropellets or as conventional freeze-dried product during an accelerated stability study using incubations at 25 °C and 37 °C over several weeks. The results from this investigation demonstrate the ability to formulate live-attenuated viruses in micropellets. Pharmaceutical applications of this novel vaccine solid form are discussed.


Assuntos
Vacina contra Febre Amarela/química , Animais , Química Farmacêutica/métodos , Estabilidade de Medicamentos , Excipientes/química , Liofilização/métodos , Vacinas Atenuadas/química , Células Vero
9.
Nat Med ; 25(8): 1218-1224, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308506

RESUMO

Flaviviral infections result in a wide spectrum of clinical outcomes, ranging from asymptomatic infection to severe disease. Although the correlates of severe disease have been explored1-4, the pathophysiology that differentiates symptomatic from asymptomatic infection remains undefined. To understand the molecular underpinnings of symptomatic infection, the blood transcriptomic and metabolomic profiles of individuals were examined before and after inoculation with the live yellow fever viral vaccine (YF17D). It was found that individuals with adaptive endoplasmic reticulum (ER) stress and reduced tricarboxylic acid cycle activity at baseline showed increased susceptibility to symptomatic outcome. YF17D infection in these individuals induced maladaptive ER stress, triggering downstream proinflammatory responses that correlated with symptomatic outcome. The findings of the present study thus suggest that the ER stress response and immunometabolism underpin symptomatic yellow fever and possibly even other flaviviral infections. Modulating either ER stress or metabolism could be exploited for prophylaxis against symptomatic flaviviral infection outcome.


Assuntos
Estresse do Retículo Endoplasmático , Vacina contra Febre Amarela/imunologia , Febre Amarela/metabolismo , Adulto , Ciclo do Ácido Cítrico , Suscetibilidade a Doenças , Humanos , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/metabolismo , Vacinas Atenuadas/imunologia , Febre Amarela/etiologia
11.
Mem Inst Oswaldo Cruz ; 114: e180509, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066755

RESUMO

BACKGROUND: The outbreak of sylvatic Yellow Fever (SYF) in humans during 2016-2017 in Brazil is one of the greatest in the history of the disease. The occurrence of the disease in areas with low vaccination coverage favoured the dissemination of the disease; therefore, it is necessary to identify the areas vulnerability to the YF virus (YFV) to assist in the adoption of preventive measures. OBJECTIVE: To correlate the physical-environmental elements associated with the occurrence of SYF in humans via a multicriteria analysis. METHODS: For the multicriteria analysis, preponderant elements related to SYF occurrences, including soil usage and coverage, temperature, precipitation, altitude, mosquito transmitters, and non-human primate occurrence areas, were considered. The results were validated by assessing the correlation between the incidence of SYF and the vulnerable areas identified in the multicriteria analysis. RESULTS: Two regions with different vulnerability to the occurrence of the disease were identified in the multicriteria analysis, with emphasis on the southern areas of the state of São Paulo northeast areas of Minas Gerais, and the entire states of Rio de Janeiro and Espírito Santo. The map of SYF vulnerability obtained in the multicriteria analysis coincides with the areas in which cases of the disease have been recorded. The regions that presented the greatest suitability were in fact the municipalities with the highest incidence. MAIN CONCLUSIONS: The multicriteria analysis revealed that the elements that were used are suited for and consistent in the prediction of the areas that are vulnerable to SYF. The results obtained indicate the proximity of the areas that are most vulnerable to the disease to densely populated areas where an Aedes aegypti infestation was observed, which confers a high risk of re-urbanisation of YF.


Assuntos
Aedes/virologia , Febre Amarela/transmissão , Animais , Brasil/epidemiologia , Doenças Endêmicas/prevenção & controle , Sistemas de Informação Geográfica , Humanos , Densidade Demográfica , Vigilância da População , Medição de Risco , Urbanização , Febre Amarela/epidemiologia , Febre Amarela/prevenção & controle , Vacina contra Febre Amarela
12.
Travel Med Infect Dis ; 30: 25-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31075425

RESUMO

BACKGROUND: We study the association between prior yellow fever immunization and clinical outcomes of dengue infections in individuals of varying sexes and ages. Serological interactions between dengue virus and other flaviviruses could drive antibody dependent enhancement, which is associated with disease severity in dengue infections. This effect may influence disease severity in individuals subsequently affected by related flaviviruses, such as dengue. We compare the severity of dengue episodes between patients vaccinated and non-vaccinated against yellow fever. METHODS: We evaluated the severity of 11,448 lab-confirmed dengue cases reported in São José do Rio Preto, Brazil, in 7370 YF vaccinated patients compared to 4043 unvaccinated patients. We regressed dengue severity against YF vaccine status and a number of demographic, clinical, and laboratory variables as controls. We also evaluated the association between YF vaccination status and the clinical and laboratory symptoms of dengue patients. RESULTS: We did not find any evidence of increased risk for severe dengue in patients vaccinated against YF (odds ratio = 1.00; 95% confidence interval = 0.87-1.14). Most of the variables analyzed did not have a statistically significant association with YF vaccination status. CONCLUSIONS: We found no evidence that YF vaccination in dengue-endemic areas increases the risk of severe dengue fever.


Assuntos
Dengue/patologia , Vacina contra Febre Amarela/imunologia , Adolescente , Adulto , Brasil/epidemiologia , Criança , Demografia , Dengue/diagnóstico , Dengue/epidemiologia , Dengue/imunologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Vacina contra Febre Amarela/normas
13.
BMJ Case Rep ; 12(5)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31088820

RESUMO

A 35-year-old man presented to his optician with sudden onset diplopia and a 1-week history of headaches. He was noted to have sixth nerve palsy. The following day he was admitted to hospital with confusion and expressive dysphasia. He had been due to travel to Ghana on business and had received yellow fever (YF) vaccination 18 days prior to onset of headaches. His initial cerebrospinal fluid (CSF) revealed elevated protein, increased white cell count but was PCR negative for standard viral pathogens. Herpes simplex virus (HSV)-1 was detected by PCR in CSF at a very low level from a second lumbar puncture performed 6 days later, and the patient was treated for HSV meningoencephalitis. However, retrospective investigation for yellow fever vaccine-associated neurological disease revealed increasing titres of YF IgG in three serial CSF samples, and no evidence of HSV antibodies in CSF or plasma, ruling out HSV encephalitis.


Assuntos
Doenças do Sistema Nervoso/induzido quimicamente , Vacina contra Febre Amarela/efeitos adversos , Adulto , Herpesvirus Humano 1 , Humanos , Imunoglobulina G/sangue , Masculino , Doenças do Sistema Nervoso/virologia
16.
Int J Infect Dis ; 81: 4-5, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30660799

RESUMO

OBJECTIVES: This study was performed to determine whether neutralizing antibodies against yellow fever virus (YFV) generated by YFV vaccine could interfere in the specificity of dengue virus (DENV) and Zika virus (ZIKV) IgG ELISA tests. METHODS: Seventy-nine pairs of serum samples (pre- and post-vaccination), collected during the years 1997-1998 from children with no history of yellow fever disease who had been vaccinated against YFV, were tested. The seroconversion post-vaccination was evaluated through plaque reduction neutralization test (PRNT), and four different commercial ELISA kits were used for the detection of DENV and ZIKV IgG antibodies. RESULTS: A cross-reactivity rate of 3.9% with DENV IgG antibodies was found only with the Dengue Virus IgG Dx Select kit (Focus Diagnostics). CONCLUSIONS: As several countries have local transmission of multiple arboviruses, the absence of cross-reactivity or minimum cross-reactivity of YFV neutralizing antibodies with DENV and ZIKV antigens is a relevant finding, since the interpretation of sero-epidemiological investigations would be seriously impacted in many regions where YFV vaccination is mandatory.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Vacina contra Febre Amarela/imunologia , Zika virus/imunologia , Antígenos Virais , Criança , Reações Cruzadas , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G/sangue , Testes de Neutralização , Vírus da Febre Amarela/imunologia
17.
N Engl J Med ; 381(5): 444-454, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29443626

RESUMO

BACKGROUND: In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign. METHODS: We recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT50). Participants with a PRNT50 titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response. RESULTS: Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P<0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P<0.001 for both comparisons). CONCLUSIONS: A fractional dose of the 17DD yellow fever vaccine was effective at inducing seroconversion in participants who were seronegative at baseline. Titers remained above the threshold for seropositivity at 1 year after vaccination in nearly all participants who were seropositive at 1 month after vaccination. These findings support the use of fractional-dose vaccination for outbreak control. (Funded by the U.S. Agency for International Development and the Centers for Disease Control and Prevention.).


Assuntos
Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , República Democrática do Congo/epidemiologia , Surtos de Doenças , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Soroconversão , Febre Amarela/epidemiologia , Febre Amarela/imunologia , Vacina contra Febre Amarela/administração & dosagem , Vírus da Febre Amarela/isolamento & purificação , Adulto Jovem
18.
Ocul Immunol Inflamm ; 27(4): 521-523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30153765

RESUMO

Purpose: To describe two cases of anterior and intermediate uveitis following yellow fever vaccination with fractional dose. Methods: Case report. Results: Case 1: A 35 year-old healthy woman presented with unilateral anterior uveitis 10 days after the yellow fever vaccination. Testing excluded infectious and rheumatic diseases and the episode was fully recovered after a short course of topical treatment. Case 2: A 21 year-old previously healthy woman presented with blurred vision in the left eye (OS) 14 days after the yellow fever vaccination. The ophthalmic examination of the OS revealed intermediated uveitis. Testing excluded infectious and neurological diseases. After six weeks of treatment with oral prednisone, the ocular inflammation had resolved. Conclusion: Physicians should be aware of the possibility of eye inflammation following the yellow fever vaccination.


Assuntos
Retina/diagnóstico por imagem , Uveíte Anterior/etiologia , Uveíte Intermediária/etiologia , Vacinação/efeitos adversos , Vacina contra Febre Amarela/efeitos adversos , Administração Oral , Adulto , Dexametasona/administração & dosagem , Feminino , Angiofluoresceinografia , Fundo de Olho , Glucocorticoides/administração & dosagem , Humanos , Prednisona/administração & dosagem , Uveíte Anterior/diagnóstico , Uveíte Intermediária/diagnóstico , Acuidade Visual , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adulto Jovem
20.
Rio de Janeiro; s.n; 2019. xxi, 150 p. ilus.
Tese em Português | LILACS | ID: biblio-1026458

RESUMO

A vacina de febre amarela atenuada é uma das mais bem-sucedidas já desenvolvidas. Entretanto, restrições de administração para pacientes imunodeprimidos e raros eventos adversos associados são desvantagens que motivam o desenvolvimento de vacinas mais seguras. À medida que aumenta a segurança, a imunogenicidade diminui na ausência de replicação viral. Nesse contexto, adjuvantes são elementos chave na ativação da imunidade inata para modulação das respostas adaptativas e proteção. Adjuvantes de diferentes naturezas e mecanismos de ação têm sido estudados: imunoestimuladores como agonistas de TLR, carreadores de antígenos e agentes de efeito depósito. Nesse estudo pretendemos identificar adjuvantes promissores para o desenvolvimento de novos candidatos vacinais para febre amarela. Para isso, camundongos C57BL/6 foram imunizados com diferentes formulações de antígenos modelo (vírus inativado e proteínas de envelope recombinantes produzidas em diferentes sistemas de expressão) com os adjuvantes: Al(OH)3; Addavax (emulsão baseada em esqualeno); combinações de Al(OH)3 e Flagelina FliC (agonista de TLR5); e CAF01 (nanopartícula) em esquema de 2 doses (D0 e D28) ou 3 doses (D0, D14 e D28). Após a imunização, os camundongos foram desafiados com inóculo letal do vírus de febre amarela por via intracerebral para determinar as taxas de sobrevivência. Os soros foram analisados por ELISA e PRNT50 para detecção dos títulos de IgG total e anticorpos neutralizantes


O vírus FA17DD inativado apresentou o melhor desempenho como antígeno modelo, sendo capaz de induzir 100% de proteção ao desafio após imunização com 2 doses na formulação com o adjuvante Addavax e 70% de proteção na formulação com hidróxido de alumínio. Os demais adjuvantes avaliados (Al(OH)3/ Flagelina FliC e CAF01) não foram capazes de gerar incremento de proteção com os antígenos avaliados. As formulações experimentais com melhor desempenho (FA17DD inativado/Addavax e FA17DD inativado/Al(OH3) foram avaliadas em um segundo ensaio para melhor caracterização das respostas imunológicas envolvidas na proteção. Ambas foram capazes de induzir apenas níveis basais de anticorpos neutralizantes; porém altos títulos de IgG para o vírus da febre amarela com predomínio do subtipo IgG1. A caracterização das respostas celulares locais (ELISpot citocinas e células B) no sítio de inoculação nos tempos pré e pós-desafio revelou níveis superiores de IFNγ nos animais sobreviventes. Após o desafio, todos os animais sobreviventes apresentaram altos títulos de anticorpos neutralizante e IgG total, com incremento do subtipo IgG2a. O uso de Addavax como adjuvante para vacinas não vivas para febre amarela surge como uma alternativa promissora de induzir proteção com menor número de doses. A aplicação do modelo de desafio murino para febre amarela na avaliação de novos adjuvantes se mostrou uma abordagem promissora para a avaliação de novos adjuvantes para uso neste modelo, bem como na geração de conhecimentos extrapoláveis para outros candidatos vacinais em desenvolvimento. (AU)


Assuntos
Animais , Bioensaio , Proteínas Recombinantes , Vacinas de Produtos Inativados , Adjuvantes Imunológicos , Vacina contra Febre Amarela
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