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1.
Front Immunol ; 10: 1211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293563

RESUMO

The present study aims to determine whether 17DD-YF-specific humoral and cellular immunological memory is maintained 8-years after primary vaccination with subdoses (10,447IU;3,013IU;587IU;158IU;31IU). For this purpose, this follow-up study was carried out in a subset of volunteers (n = 98) originally enrolled in the dose-response study in 2009 and 46 non-vaccinated controls. Our results demonstrated that vaccinees, who had seroconverted following primary vaccination and had not been revaccinated, present similar neutralizing antibodies levels and YF-specific cellular memory, particularly CMCD4 and EMCD8 as compared to the reference full dose (27,476IU). Although, PRNT seropositivity rates were similar across subgroups (94, 82, 83, 94, 80, and 91%, correspondingly), only doses above 587IU elicited similar iterative proportion of seropositivity rates, calculated as a progressive decrease on seropositivity rates along time (89, 80, 80, and 91%, respectively) as compared to 158IU and 31IU (68 and 46%, respectively). Noteworthy were the strong positive correlations ("EMCD4,EMCD8" and "TNFCD8,IFNCD8") observed in most subdoses, except for 31IU. Major similarities underscored the preserved antibody titers and the outstanding levels of EMCD8, relevant correlates of protection for YF-specific immunity. These findings provide evidences to support the regular use of dose sparing strategy for YF vaccine in adults.

2.
J Exp Med ; 216(9): 2057-2070, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270247

RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.

3.
PLoS Negl Trop Dis ; 12(6): e0006462, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879134

RESUMO

In this investigation, machine-enhanced techniques were applied to bring about scientific insights to identify a minimum set of phenotypic/functional memory-related biomarkers for post-vaccination follow-up upon yellow fever (YF) vaccination. For this purpose, memory status of circulating T-cells (Naïve/early-effector/Central-Memory/Effector-Memory) and B-cells (Naïve/non-Classical-Memory/Classical-Memory) along with the cytokine profile (IFN/TNF/IL-5/IL-10) were monitored before-NV(day0) and at distinct time-points after 17DD-YF primary vaccination-PV(day30-45); PV(year1-9) and PV(year10-11). A set of biomarkers (eEfCD4; EMCD4; CMCD19; EMCD8; IFNCD4; IL-5CD8; TNFCD4; IFNCD8; TNFCD8; IL-5CD19; IL-5CD4) were observed in PV(day30-45), but not in NV(day0), with most of them still observed in PV(year1-9). Deficiencies of phenotypic/functional biomarkers were observed in NV(day0), while total lack of memory-related attributes was observed in PV(year10-11), regardless of the age at primary vaccination. Venn-diagram analysis pre-selected 10 attributes (eEfCD4, EMCD4, CMCD19, EMCD8, IFNCD4, IL-5CD8, TNFCD4, IFNCD8, TNFCD8 and IL-5CD4), of which the overall mean presented moderate accuracy to discriminate PV(day30-45)&PV(year1-9) from NV(day0)&PV(year10-11). Multi-parameter approaches and decision-tree algorithms defined the EMCD8 and IL-5CD4 attributes as the top-two predictors with moderated performance. Together with the PRNT titers, the top-two biomarkers led to a resultant memory status observed in 80% and 51% of volunteers in PV(day30-45) and PV(year1-9), contrasting with 0% and 29% found in NV(day0) and PV(year10-11), respectively. The deficiency of memory-related attributes observed at PV(year10-11) underscores the conspicuous time-dependent decrease of resultant memory following17DD-YF primary vaccination that could be useful to monitor potential correlates of protection in areas under risk of YF transmission.


Assuntos
Anticorpos Antivirais/sangue , Biomarcadores/sangue , Vacinação , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Vírus da Febre Amarela/imunologia , Adolescente , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Febre Amarela/imunologia , Febre Amarela/virologia , Adulto Jovem
4.
Mem Inst Oswaldo Cruz ; 110(1): 114-24, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25742271

RESUMO

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.


Assuntos
Academias e Institutos/história , Vacinas Bacterianas/história , Ensaios Clínicos como Assunto/história , Vacinas Protozoárias/história , Vacinas Virais/história , Vacinas Bacterianas/uso terapêutico , Brasil , História do Século XX , História do Século XXI , Humanos , Vacinas Protozoárias/uso terapêutico , Pesquisa , Tecnologia Farmacêutica/métodos , Tecnologia Farmacêutica/tendências , Vacinas Virais/uso terapêutico
5.
Mem. Inst. Oswaldo Cruz ; 110(1): 114-124, 03/02/2015. tab
Artigo em Inglês | LILACS | ID: lil-741621

RESUMO

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.


Assuntos
Animais , Ração Animal/efeitos adversos , Proteínas na Dieta/química , Modelos Biológicos , Proantocianidinas/química , Rúmen/metabolismo , Brassica rapa/química , Precipitação Química , Proteínas na Dieta/metabolismo , Fermentação , Fabaceae/efeitos adversos , Fabaceae/química , Frutas/efeitos adversos , Frutas/química , Estrutura Molecular , Peso Molecular , Concentração Osmolar , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Proantocianidinas/efeitos adversos , Proantocianidinas/metabolismo , Ruminantes , Ribulose-Bifosfato Carboxilase/química , Ribulose-Bifosfato Carboxilase/metabolismo , Rúmen/microbiologia , Solubilidade , Estereoisomerismo , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo
6.
Mem. Inst. Oswaldo Cruz ; 109(3): 335-339, 06/2014. tab
Artigo em Inglês | LILACS | ID: lil-711723

RESUMO

A non-controlled longitudinal study was conducted to evaluate the combined vaccine against measles, mumps and rubella (MMR) immunogenicity in 150 children vaccinated in the routine of three health units in the city of Rio de Janeiro, Brazil, 2008-2009, without other vaccines administered during the period from 30 days before to 30 days after vaccination. A previous study conducted in Brazil in 2007, in 1,769 children ranging from 12-15 months of age vaccinated against yellow fever and MMR simultaneously or at intervals of 30 days or more between doses, had shown low seroconversion for mumps regardless of the interval between administration of the two vaccines. The current study showed 89.5% (95% confidence interval: 83.3; 94.0) seroconversion rate for mumps. All children seroconverted for measles and rubella. After revaccination, high antibody titres and seroconversion rates were achieved against mumps. The results of this study and others suggest that two MMR doses confer optimal immunoresponses for all three antigens and the possible need for additional doses should be studied taking into account not only serological, but also epidemiological data, as there is no serological correlate of protection for mumps.


Assuntos
Feminino , Humanos , Lactente , Masculino , Anticorpos Antivirais/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Caxumba/imunologia , Soroconversão , Anticorpos Antivirais/sangue , Brasil , Esquemas de Imunização , Estudos Longitudinais , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Sarampo/imunologia , Caxumba/prevenção & controle , Rubéola (Sarampo Alemão)/imunologia
7.
Mem Inst Oswaldo Cruz ; 109(3): 335-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24821058

RESUMO

A non-controlled longitudinal study was conducted to evaluate the combined vaccine against measles, mumps and rubella (MMR) immunogenicity in 150 children vaccinated in the routine of three health units in the city of Rio de Janeiro, Brazil, 2008-2009, without other vaccines administered during the period from 30 days before to 30 days after vaccination. A previous study conducted in Brazil in 2007, in 1,769 children ranging from 12-15 months of age vaccinated against yellow fever and MMR simultaneously or at intervals of 30 days or more between doses, had shown low seroconversion for mumps regardless of the interval between administration of the two vaccines. The current study showed 89.5% (95% confidence interval: 83.3; 94.0) seroconversion rate for mumps. All children seroconverted for measles and rubella. After revaccination, high antibody titres and seroconversion rates were achieved against mumps. The results of this study and others suggest that two MMR doses confer optimal immunoresponses for all three antigens and the possible need for additional doses should be studied taking into account not only serological, but also epidemiological data, as there is no serological correlate of protection for mumps.


Assuntos
Anticorpos Antivirais/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Caxumba/imunologia , Soroconversão , Anticorpos Antivirais/sangue , Brasil , Feminino , Humanos , Esquemas de Imunização , Lactente , Estudos Longitudinais , Masculino , Sarampo/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Caxumba/prevenção & controle , Rubéola (Sarampo Alemão)/imunologia
8.
Vaccine ; 32(49): 6676-82, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-24837504

RESUMO

Neurological adverse events following administration of the 17DD substrain of yellow fever vaccine (YEL-AND) in the Brazilian population are described and analyzed. Based on information obtained from the National Immunization Program through passive surveillance or intensified passive surveillance, from 2007 to 2012, descriptive analysis, national and regional rates of YFV associated neurotropic, neurological autoimmune disease, and reporting rate ratios with their respective 95% confidence intervals were calculated for first time vaccinees stratified on age and year. Sixty-seven neurological cases were found, with the highest rate of neurological adverse events in the age group from 5 to 9 years (2.66 per 100,000 vaccine doses in Rio Grande do Sul state, and 0.83 per 100,000 doses in national analysis). Two cases had a combination of neurotropic and autoimmune features. This is the largest sample of YEL-AND already analyzed. Rates are similar to other recent studies, but on this study the age group from 5 to 9 years of age had the highest risk. As neurological adverse events have in general a good prognosis, they should not contraindicate the use of yellow fever vaccine in face of risk of infection by yellow fever virus.


Assuntos
Doenças do Sistema Nervoso Central/induzido quimicamente , Vacina contra Febre Amarela/administração & dosagem , Vacina contra Febre Amarela/efeitos adversos , Febre Amarela/prevenção & controle , Adolescente , Adulto , Fatores Etários , Idoso , Brasil , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Cien Saude Colet ; 16(2): 445-58, 2011 Feb.
Artigo em Português | MEDLINE | ID: mdl-21340320

RESUMO

The smallpox worldwide eradication was the major world public health achievement. The binomial - vaccines and immunization - continues to demonstrate very high performance in the prevention and control of other diseases preventable by vaccination. The new global initiatives on vaccination, such as GAVI, have made possible the introduction of new and important vaccines preventing million of children deaths in the poorest countries in the world. The National Immunization Program of Brazil is also being strengthened, with the introduction of several new vaccines into the basic calendar as rotavirus, pneumococcal and meningococcal conjugated and H1N1 in national campaign, covering the population at risk. With the discovery of high valued vaccines, the big pharmaceutical companies became interested in this area, investing heavily in technological innovation, making fusions, acquisitions and technological partnerships. Brazil has also established a new innovation policy, creating new laws as well as subsidizing projects in technological innovation and modernization of production infra-structure.


Assuntos
Imunização , Vacinação , Vacinas , Humanos , Imunização/normas , Vacinação/normas
11.
Ciênc. saúde coletiva ; 16(2): 445-458, fev. 2011. graf, tab
Artigo em Português | LILACS | ID: lil-582437

RESUMO

A erradicação da varíola foi a maior conquista da saúde pública mundial. E o binômio vacinas e imunizações continua a demonstrar alto desempenho na prevenção e no controle de outras doenças imunopreveníveis. As novas iniciativas globais em vacinação, como a GAVI, vêm possibilitando a introdução de novas vacinas e salvando vidas de milhares de crianças nos países mais pobres do mundo. O Programa Nacional de Imunizações (PNI) do Brasil também vem sendo fortalecido com a incorporação de novas vacinas no seu calendário de imunizações, como a vacina contra rotavírus, pneumococos conjugada, meningite meningocócica do sorogrupo C conjugada, além do H1N1 para as populações de maior risco. Com o descobrimento de novas vacinas de alto valor agregado, os grandes laboratórios multinacionais despertaram para este segmento farmacêutico e buscam a liderança da área, investindo maciçamente em inovação tecnológica, além de realizar fusões, aquisições e parcerias tecnológicas. O Brasil também vem se fortalecendo, tendo criado marcos reguladores e financiando projetos de inovação tecnológica e modernização da infraestrutura de produção.


The smallpox worldwide eradication was the major world public health achievement. The binomial vaccines and immunization continues to demonstrate very high performance in the prevention and control of other diseases preventable by vaccination. The new global initiatives on vaccination, such as GAVI, have made possible the introduction of new and important vaccines preventing million of children deaths in the poorest countries in the world. The National Immunization Program of Brazil is also being strengthened, with the introduction of several new vaccines into the basic calendar as rotavirus, pneumococcal and meningococcal conjugated and H1N1 in national campaign, covering the population at risk. With the discovery of high valued vaccines, the big pharmaceutical companies became interested in this area, investing heavily in technological innovation, making fusions, acquisitions and technological partnerships. Brazil has also established a new innovation policy, creating new laws as well as subsidizing projects in technological innovation and modernization of production infra-structure.


Assuntos
Humanos , Imunização , Vacinação , Vacinas , Imunização/normas , Vacinação/normas
12.
Mem Inst Oswaldo Cruz ; 103(7): 711-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19057823

RESUMO

A randomized, double-blinded study evaluating the immunogenicity, safety and consistency of production of a combined diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine entirely produced in Brazil by Bio-Manguinhos and Instituto Butantan (DTP/Hib-BM) was undertaken. The reference vaccine had the same DTP vaccine but the Hib component was produced using purified materials supplied by GlaxoSmithKline (DTP/Hib-GSK), which is registered and has supplied the Brazilian National Immunization Program for over more than five years. One thousand infants were recruited for the study and received vaccinations at two, four and six months of age. With respect to immunogenicity, the vaccination protocol was followed in 95.6% and 98.4% of infants in the DTP/Hib-BM and DTP/Hib-GSK groups, respectively. For the Hib component of the study, there was 100% seroprotection (> or =0.15 microg/mL) with all three lots of DTP/Hib-BM and DTP/Hib-GSK. The geometric mean titer (GMT) was 9.3 microg/mL, 10.3 microg/mL and 10.3 microg/mL for lots 1, 2 and 3 of DTP/Hib-BM, respectively, and the GMT was 11.3 g/mL for DTP/Hib-GSK. For diphtheria, tetanus and pertussis, seroprotection was 99.7%, 100% and 99.9%, respectively, for DTP/Hib-BM, three lots altogether and 99.2%, 100% and 100% for DTP/Hib-GSK. GMTs were similar across all lots and vaccines. Adverse events rates were comparable among the vaccine groups. The Brazilian DTP/Hib vaccine demonstrated an immunogenicity and reactogenicity profile similar to that of the reference vaccine.


Assuntos
Vacina contra Difteria, Tétano e Coqueluche/imunologia , Difteria/prevenção & controle , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/imunologia , Tétano/prevenção & controle , Coqueluche/prevenção & controle , Bordetella pertussis/imunologia , Clostridium tetani/imunologia , Corynebacterium diphtheriae/imunologia , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Método Duplo-Cego , Feminino , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/efeitos adversos , Haemophilus influenzae tipo b/imunologia , Humanos , Lactente , Masculino , Fatores de Tempo
13.
Mem. Inst. Oswaldo Cruz ; 103(7): 711-718, Nov. 2008. ilus, tab
Artigo em Inglês | LILACS | ID: lil-498381

RESUMO

A randomized, double-blinded study evaluating the immunogenicity, safety and consistency of production of a combined diphtheria-tetanus-pertussis-Haemophilus influenzae type b vaccine entirely produced in Brazil by Bio-Manguinhos and Instituto Butantan (DTP/Hib-BM) was undertaken. The reference vaccine had the same DTP vaccine but the Hib component was produced using purified materials supplied by GlaxoSmithKline (DTP/Hib-GSK), which is registered and has supplied the Brazilian National Immunization Program for over more than five years. One thousand infants were recruited for the study and received vaccinations at two, four and six months of age. With respect to immunogenicity, the vaccination protocol was followed in 95.6 percent and 98.4 percent of infants in the DTP/Hib-BM and DTP/Hib-GSK groups, respectively. For the Hib component of the study, there was 100 percent seroprotection (>0.15 µg/mL) with all three lots of DTP/Hib-BM and DTP/Hib-GSK. The geometric mean titer (GMT) was 9.3 µg/mL, 10.3 µg/mL and 10.3 µg/mL for lots 1, 2 and 3 of DTP/Hib-BM, respectively, and the GMT was 11.3 g/mL for DTP/Hib-GSK. For diphtheria, tetanus and pertussis, seroprotection was 99.7 percent, 100 percent and 99.9 percent, respectively, for DTP/Hib-BM, three lots altogether and 99.2 percent, 100 percent and 100 percent for DTP/Hib-GSK. GMTs were similar across all lots and vaccines. Adverse events rates were comparable among the vaccine groups. The Brazilian DTP/Hib vaccine demonstrated an immunogenicity and reactogenicity profile similar to that of the reference vaccine.


Assuntos
Feminino , Humanos , Lactente , Masculino , Vacina contra Difteria, Tétano e Coqueluche/imunologia , Difteria/prevenção & controle , Infecções por Haemophilus/prevenção & controle , Vacinas Anti-Haemophilus/imunologia , Tétano/prevenção & controle , Coqueluche/prevenção & controle , Bordetella pertussis/imunologia , Clostridium tetani/imunologia , Corynebacterium diphtheriae/imunologia , Método Duplo-Cego , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/efeitos adversos , Haemophilus influenzae tipo b/imunologia , Fatores de Tempo
14.
Mem Inst Oswaldo Cruz ; 102(1): 117-20, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17294011

RESUMO

The objective of this paper is to propose a protocol to analyze blood samples in yellow fever 17DD vaccinated which developed serious adverse events. We investigated whether or not the time between sample collection and sample processing could interfere in lymphocyte subset percentage, for it is often impossible to analyze blood samples immediately after collection due to transport delay from collection places to the flow cytometry facility. CD4+CD38+ T, CD8+CD38+ T, CD3+ T, CD19+ B lymphocyte subsets were analyzed by flow cytometry in nine healthy volunteers immediately after blood collection and after intervals of 24 and 48 h. The whole blood lysis method and gradient sedimentation by Histopaque were applied to isolate peripheral blood mononuclear cells for flow cytometry analyses. With the lysis method, there was no significant change in lymphocyte subset percentage between the two time intervals (24 and 48 h). In contrast, when blood samples were processed by Histopaque gradient sedimentation, time intervals for sample processing influenced the percentage in T lymphocyte subsets but not in B cells. From the results obtained, we could conclude that the whole blood lysis method is more appropriate than gradient sedimentation by Histopaque for immunophenotyping of blood samples collected after serious adverse events, due to less variation in the lymphocyte subset levels with respect to the time factor.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos T/imunologia , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Citometria de Fluxo , Humanos , Imunofenotipagem , Contagem de Linfócitos , Fatores de Tempo , Febre Amarela/prevenção & controle , Vacina contra Febre Amarela/efeitos adversos
15.
Mem. Inst. Oswaldo Cruz ; 102(1): 117-120, Feb. 2007. graf
Artigo em Inglês | LILACS | ID: lil-440634

RESUMO

The objective of this paper is to propose a protocol to analyze blood samples in yellow fever 17DD vaccinated which developed serious adverse events. We investigated whether or not the time between sample collection and sample processing could interfere in lymphocyte subset percentage, for it is often impossible to analyze blood samples immediately after collection due to transport delay from collection places to the flow cytometry facility. CD4+CD38+ T, CD8+CD38+ T, CD3+ T, CD19+ B lymphocyte subsets were analyzed by flow cytometry in nine healthy volunteers immediately after blood collection and after intervals of 24 and 48 h. The whole blood lysis method and gradient sedimentation by Histopaque were applied to isolate peripheral blood mononuclear cells for flow cytometry analyses. With the lysis method, there was no significant change in lymphocyte subset percentage between the two time intervals (24 and 48 h). In contrast, when blood samples were processed by Histopaque gradient sedimentation, time intervals for sample processing influenced the percentage in T lymphocyte subsets but not in B cells. From the results obtained, we could conclude that the whole blood lysis method is more appropriate than gradient sedimentation by Histopaque for immunophenotyping of blood samples collected after serious adverse events, due to less variation in the lymphocyte subset levels with respect to the time factor.


Assuntos
Humanos , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos T/imunologia , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Citometria de Fluxo , Imunofenotipagem , Contagem de Linfócitos , Fatores de Tempo , Vacina contra Febre Amarela/efeitos adversos , Febre Amarela/prevenção & controle
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