Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody

Submitted by Nuzia Santos ([email protected]) on 2015-01-08T11:26:26Z No. of bitstreams: 1 Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody.pdf: 966125 bytes, checksum: 28568df442b4339a0d66df8a67105883 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-01-08T11:28:11Z (GMT) No. of bitstreams: 1 Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody.pdf: 966125 bytes, checksum: 28568df442b4339a0d66df8a67105883 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-01-08T11:35:53Z (GMT) No. of bitstreams: 1 Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody.pdf: 966125 bytes, checksum: 28568df442b4339a0d66df8a67105883 (MD5)Made available in DSpace on 2015-01-08T11:35:53Z (GMT). No. of bitstreams: 1 Cytokine Signatures of Innate and Adaptive Immunity in 17DD Yellow Fever Vaccinated Children and Its Association With the Level of Neutralizing Antibody.pdf: 966125 bytes, checksum: 28568df442b4339a0d66df8a67105883 (MD5) Previous issue date: 2011Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilUniversidade Federal de Ouro Preto. Ouro Preto, MG, BrasilFundação Oswaldo Cruz. Escola Nacional de Saúde Pública. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Rio de Janeiro, RJ, BrasilSecretaria de Estado de Saúde de Minas Gerais. Belo Horizonte, MG, BrasilSecretaria de Estado de Saúde de Minas Gerais. Belo Horizonte, MG, BrasilUniversidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Hospital das Clínicas. Ribeirão Preto, SP, BrasilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Departamento de Propedêutica Complementar Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilBackground. The live attenuated yellow fever (YF) vaccines have been available for decades and are considered highly effective and one of the safest vaccines worldwide. Methods. The impact of YF-17DD-antigens recall on cytokine profiles of YF-17DD-vaccinated children were characterized using short-term cultures of whole blood samples and single-cell flow cytometry. This study enrolled seroconverters and nonseroconverters after primovaccination (PV-PRNT1 and PV-PRNT2), seroconverters after revaccination (RV-PRNT1), and unvaccinated volunteers (UV-PRNT2). Results. The analysis demonstrated in the PV-PRNT1 group a balanced involvement of pro-inflammatory/ regulatory adaptive immunity with a prominent participation of innate immunity pro-inflammatory events (IL-121 and TNF-a1 NEU and MON). Using the PV-PRNT1 cytokine signature as a reference profile, PV-PRNT2 presented a striking lack of innate immunity proinflammatory response along with an increased adaptive regulatory profile (IL-41CD41 T cells and IL-101 and IL-51CD81 T cells). Conversely, the RV-PRNT1 shifted the overall cytokine signatures toward an innate immunity pro-inflammatory profile and restored the adaptive regulatory response. Conclusions. The data demonstrated that the overall cytokine signature was associated with the levels of PRNT antibodies with a balanced innate/adaptive immunity with proinflammatory/regulatory profile as the hallmark of PV-PRNTMEDIUM1, whereas a polarized regulatory response was observed in PV-PRNT2 and a prominent proinflammatory signature was the characteristic of PV-PRNTHIGH1

17DD and 17D-213/77 yellow fever substrains trigger a balanced cytokine profile in primary vaccinated children

Submitted by Nuzia Santos ([email protected]) on 2014-03-07T13:46:37Z No. of bitstreams: 1 17DD.pdf: 2852641 bytes, checksum: e43b3e257ffaa87a20d7866b9fdc814d (MD5)Made available in DSpace on 2014-03-07T13:46:37Z (GMT). No. of bitstreams: 1 17DD.pdf: 2852641 bytes, checksum: e43b3e257ffaa87a20d7866b9fdc814d (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Biomarcadores de Diagnóstico e Monitoração. Belo Horizonte, MG, BrasilUniversidade Federal de Ouro Preto. Núcleo de Pesquisas em Ciências Biológicas. Ouro Preto, MG, BrasilUniversidade Federal de Ouro Preto. Núcleo de Pesquisas em Ciências Biológicas. Ouro Preto, MG, BrasilFundação Oswaldo Cruz. Escola Nacional de Saúde Pública. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos, Bio-Manguinhos. Rio de Janeiro, RJ, BrasilGoverno do Estado de Minas Gerais. Secretaria de Estado de Saúde. Belo Horizonte, MG, BrasilGoverno do Estado de Minas Gerais. Secretaria de Estado de Saúde. Belo Horizonte, MG, BrasilUniversidade de São Paulo. Faculdade de Medicina de Ribeirão Preto. Hospital das Clínicas. Ribeirão Preto, SP, BrasilFundação Oswaldo Cruz. Diretoria Regional de Brasília. Brasília, DF, BrasilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Departamento de Propedêutica Complementar. Belo Horizonte, MG, BrasilBACKGROUND: This study aimed to compare the cytokine-mediated immune response in children submitted to primary vaccination with the YF-17D-213/77 or YF-17DD yellow fever (YF) substrains. METHODS: A non-probabilistic sample of eighty healthy primary vaccinated (PV) children was selected on the basis of their previously known humoral immune response to the YF vaccines. The selected children were categorized according to their YF-neutralizing antibody titers (PRNT) and referred to as seroconverters (PV-PRNT(+)) or nonseroconverters (PV-PRNT(-)). Following revaccination with the YF-17DD, the PV-PRNT(-) children (YF-17D-213/77 and YF-17DD groups) seroconverted and were referred as RV-PRNT(+). The cytokine-mediated immune response was investigated after short-term in vitro cultures of whole blood samples. The results are expressed as frequency of high cytokine producers, taking the global median of the cytokine index (YF-Ag/control) as the cut-off. RESULTS: The YF-17D-213/77 and the YF-17DD substrains triggered a balanced overall inflammatory/regulatory cytokine pattern in PV-PRNT(+), with a slight predominance of IL-12 in YF-17DD vaccinees and a modest prevalence of IL-10 in YF-17D-213/77. Prominent frequency of neutrophil-derived TNF-α and neutrophils and monocyte-producing IL-12 were the major features of PV-PRNT(+) in the YF-17DD, whereas relevant inflammatory response, mediated by IL-12(+)CD8(+) T cells, was the hallmark of the YF-17D-213/77 vaccinees. Both substrains were able to elicit particular but relevant inflammatory events, regardless of the anti-YF PRNT antibody levels. PV-PRNT(-) children belonging to the YF-17DD arm presented gaps in the inflammatory cytokine signature, especially in terms of the innate immunity, whereas in the YF-17D-213/77 arm the most relevant gap was the deficiency of IL-12-producing CD8(+)T cells. Revaccination with YF-17DD prompted a balanced cytokine profile in YF-17DD nonresponders and a robust inflammatory profile in YF-17D-213/77 nonresponders. CONCLUSION: Our findings demonstrated that, just like the YF-17DD reference vaccine, the YF-17D-213/77 seed lot induced a mixed pattern of inflammatory and regulatory cytokines, supporting its universal use for immunization

Flowchart of selection and follow-up of the Study Population from the Primary Target Sample.

<p>A total of 3,060 children, 9–12 months-old were elected for an epidemiological studies reported elsewhere <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049828#pone.0049828-Collaborative1" target="_blank">[14]</a> and referred as “Primary Target Sample”. The Clinical Trial design is highlighted by dashed format. The study population enrolled in the present investigation was selected from the “Primary Target Sample” according to the PRNT results and comprise 30 PV-PRNT⁺ and 10 PV-PRNT⁻ individuals on each experimental arm (17DD and 17D-213/77), reaching a total of 80 volunteers. The current Immunological Study design is highlighted by solid format.</p

Comparative analysis of the cytokine signatures of innate and adaptive immunity triggered by the YF-17DD and YF-17D-213/77 substrains upon the <i>in vitro</i> recall of whole blood leukocytes from seroconverter children (PV-PRNT⁺) with specific YF-Ag.

<p>The diagrams highlight each leukocyte subsets with distinct tags as they display low (white rectangle) or high (black rectangle = inflammatory, gray rectangle = regulatory) cytokine producers (top panel). The ascendant frequency of volunteers with high cytokine indexes of the innate and adaptive immunity was assembled for each experimental arm and is demonstrated by bar graphs (medium panel). Comparative analysis of the overall cytokine patterns of YF-17DD (lines with black or gray triangles) and YF-17D-213/77 (lines with black or gray squares) vaccinees were further compared by overlapping the ascendant cytokine curves (bottom panel). Dotted lines highlight the 25^th and 50^th percentiles used as reference for comparative analysis. *Differences were considered relevant when the frequency for a given cytokine emerged outside the 50^th percentile as compared to the reference cytokine pattern or signature.</p

Impact of serum titers of anti-YF neutralizing antibodies on the cytokine-mediated immune response triggered by the YF-17DD and YF-17D-213/77 substrains upon <i>in vitro</i> recall of whole blood leukocytes from seroconverter children (PV-PRNT⁺) with specific YF-Ag.

<p>The PRNT⁺ groups from each experimental arm were first categorized into two subgroups referred to as PV-PRNT^MEDIUM+ (2.5≤ serum titers ≤3.5 log₁₀ mIU/mL) and PV-PRNT^HIGH+ (serum titers >3.5 log₁₀ mIU/mL). The cytokine profile of the PV-PRNT^MEDIUM+ and PV-PRNT^HIGH+ subgroups were evaluated, considering relevant the percentages of a given inflammatory cytokine that emerged higher than the 50^th percentile, as indicate by an upward arrow (↑).</p

Comparative inflammatory and regulatory cytokine signatures triggered by the YF-17DD and YF-17D-213/77 substrains upon the <i>in vitro</i> recall of whole blood leukocytes from (A) seroconverter (PV-PRNT⁺) and nonseroconverter primary vaccinees (PV-PRNT⁻) as well as (B) seroconverter revaccinees (RV-PRNT⁺) with specific YF-Ag.

<p>The ascendant frequency of volunteers with high inflammatory and regulatory cytokine indexes was assembled for each experimental arm and demonstrated by bar graphs. Comparative analysis between PV-PRNT⁺, PV-PRNT⁻, and RV-PRNT⁺ within the same experimental arm was performed taking the ascendant cytokine curve of the YF-17DD (lines with black or gray triangles) or YF-17D-213/77 (lines with black or gray squares) groups as reference. #Differences were considered relevant when the percentage of a given cytokine emerged below the quartile of the reference cytokine signatures.</p

Short-lived immunity after 17DD Yellow Fever single dose indicates that booster vaccination may be required to guarantee protective immunity in children

Submitted by Priscila Nascimento ([email protected]) on 2019-10-01T19:14:22Z No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5)Approved for entry into archive by Priscila Nascimento ([email protected]) on 2019-10-01T19:54:22Z (GMT) No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5)Made available in DSpace on 2019-10-01T19:54:22Z (GMT). No. of bitstreams: 1 Short-Lived_Immunity_After_17DD_Yellow_Fever_Singl.pdf: 3383889 bytes, checksum: 0a90002bb16cb94aad75a9789f4bd242 (MD5) Previous issue date: 2019Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Fisiologia e Biofísica. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Secretaria Municipal de Saúde de Belo Horizonte. Belo Horizonte, MG, Brasil.Secretaria do Estado de Saúde de Minas Gerais. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil.Universidade de Brasília. Faculdade de Medicina. Brasília, DF, Brasil.Instituto Evandro Chagas. Ananindeua, PA, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de Imunização e Doenças Transmissíveis. Brasília, DF, Brasil.Ministério da Saúde. Secretaria de Vigilância em Saúde. Programa Nacional de Imunizações. Brasília, DF, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil.A vacinação contra a febre amarela (YF) é recomendada para pessoas que vivem em áreas endêmicas e representa a estratégia mais eficaz para reduzir o risco de infecção. Estudos anteriores alertaram que os regimes de reforço devem ser considerados para garantir a persistência a longo prazo dos componentes de memória específicos da 17DD-YF em adultos que vivem em áreas com circulação do vírus da YF. Considerando as menores taxas de soroconversão observadas em crianças (9 a 12 meses de idade) em comparação aos adultos, este estudo foi desenvolvido para acessar a duração da imunidade em crianças vacinadas em dose única em um período de 10 anos de seção transversal . Os níveis de anticorpos neutralizantes (PRNT) e o status fenotípico / de memória funcional das células T e B foram medidos no início, 30 a 45 dias, 1, 2, 4, 7 e 10 anos após a vacinação primária. Os resultados revelaram que uma dose única induziu 85% de soropositividade entre 30 e 45 dias e uma diminuição progressiva dependente do tempo foi observada em apenas 2 anos e diminui para valores críticos (abaixo de 60%) em períodos de tempo ≥ 4 anos . Além disso, a imunidade celular específica de YF de curta duração, mediada pelas células T e B de memória, também foi observada após 4 anos. A análise de probabilidade prevista e a memória resultante enfatizam que os correlatos de proteção (PRNT; células T CD8 + com memória efetiva; células B com memória não clássica) diminuem para valores críticos dentro de ≥4 anos após a vacinação primária. Juntos, esses resultados demonstram claramente o declínio da resposta da memória específica da 17DD-YF ao longo do tempo em crianças vacinadas principalmente entre 9 e 12 meses de idade e suportam a necessidade de um regime de reforço para garantir a persistência a longo prazo dos componentes da memória para crianças que vivem em áreas com alto risco de transmissão YF.The Yellow Fever (YF) vaccination is recommended for people living in endemic areas and represents the most effective strategy to reduce the risk of infection. Previous studies have warned that booster regimens should be considered to guarantee the long-term persistence of 17DD-YF-specific memory components in adults living in areas with YF-virus circulation. Considering the lower seroconversion rates observed in children (9–12 months of age) as compared to adults, this study was designed in order to access the duration of immunity in single-dose vaccinated children in a 10-years cross-sectional time-span. The levels of neutralizing antibodies (PRNT) and the phenotypic/functional memory status of T and B-cells were measured at a baseline, 30–45 days, 1, 2, 4, 7, and 10 years following primary vaccination. The results revealed that a single dose induced 85% of seropositivity at 30–45 days and a progressive time-dependent decrease was observed as early as 2 years and declines toward critical values (below 60%) at time-spans of ≥4-years. Moreover, short-lived YF-specific cellular immunity, mediated by memory T and B-cells was also observed after 4-years. Predicted probability and resultant memory analysis emphasize that correlates of protection (PRNT; effector memory CD8+ T-cells; non-classical memory B-cells) wane to critical values within ≥4-years after primary vaccination. Together, these results clearly demonstrate the decline of 17DD-YF-specific memory response along time in children primarily vaccinated at 9–12 months of age and support the need of booster regimen to guarantee the long-term persistence of memory components for children living in areas with high risk of YF transmission

Immune response induced by standard and fractional doses of 17DD yellow fever vaccine

Abstract The re-emergence of yellow fever (YF) urged new mass vaccination campaigns and, in 2017, the World Health Organization approved the use of the fractional dose (FD) of the YF vaccine due to stock shortage. In an observational cross-sectional investigation, we have assessed viremia, antibodies, soluble mediators and effector and memory T and B-cells induced by primary vaccination of volunteers with FD and standard dose (SD). Similar viremia and levels of antibodies and soluble markers were induced early after immunization. However, a faster decrease in the latter was observed after SD. The FD led to a sustained expansion of helper T-cells and an increased expression of activation markers on T-cells early after vaccination. Although with different kinetics, expansion of plasma cells was induced upon SD and FD immunization. Integrative analysis reveals that FD induces a more complex network involving follicular helper T cells and B-cells than SD. Our findings substantiate that FD can replace SD inducing robust correlates of protective immune response against YF