Duration of post-vaccination immunity to yellow fever in volunteers ten years after a dose-response study - A complementary study.

A single dose of standard yellow fever (YF) vaccine is considered to provide life-long protection. In this study, we evaluate the seropositivity conferred by lower doses 10 years post-vaccination. In 2009, Bio-Manguinhos/Fiocruz performed a dose-response study with the 17DD yellow fever vaccine, administering the vaccine in the usual mean dose of 27.476 IU and in decreasing doses (10.447 IU, 3.013 IU, 587 IU, 158 IU and 31 IU), with the usual volume and route (0,5 ml subcutaneous). The decreasing doses were obtained by dilution in the laboratory of the manufacturer and the lots in test had standard quality control and were produced by good manufacturing practices (GMP). Around 30 days after the vaccination, doses down to 587 IU had similar immunogenicity and the 158 IU and 31 IU were inferior to the full dose. The seropositivity was maintained for 10 months, except on the 31 IU group. Eight years after, 85 % of 318 participants evaluated in a follow-up, maintained seropositivity that was similar across groups. Consistently, antibody titers in the reduced-dose groups were also comparable to those of the full-dose group. The current study, 10 years later, showed similarity between the vaccine groups (six arms who received the YF vaccine in decreasing doses: 27.476 IU, 10.447 IU, 3.013 IU, 587 IU, 158 IU, 31 IU) both in relation of seropositivity and in the evaluation of the geometric mean titers. The seropositivity rates across subgroups were 83,1%, 90 %, 87 %, 93 %, 83,8% and 85 %, correspondingly. These findings provides further support to the long-term immunogenicity of lower doses. Clinical trial registry: NCT04416477.

Comprehensive landscape of neutralizing antibody and cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF primary vaccination in adults.

The present study aimed at evaluating the YF-specific neutralizing antibody profile besides a multiparametric analysis of phenotypic/functional features of cell-mediated response elicited by the 1/5 fractional dose of 17DD-YF vaccine, administered as a single subcutaneous injection. The immunological parameters of each volunteer was monitored at two time points, referred as: before (Day 0) [Non-Vaccinated, NV(D0)] and after vaccination (Day 30-45) [Primary Vaccinees, PV(D30-45)]. Data demonstrated high levels of neutralizing antibodies for PV(D30-45) leading to a seropositivity rate of 93%. A broad increase of systemic soluble mediators with a mixed profile was also observed for PV(D30-45), with IFN-γ and TNF-α presenting the highest baseline fold changes. Integrative network mapping of soluble mediators showed increased correlation numbers in PV(D30-45) as compared to NV(D0) (532vs398). Moreover, PV(D30-45) exhibited increased levels of Terminal Effector (CD45RA+CCR7-) CD4+ and CD8+ T-cells and Non-Classical memory B-cells (IgD+CD27+). Dimensionality reduction of Mass Cytometry data further support these findings. A polyfunctional cytokine profile (TNF-α/IFN-γ/IL-10/IL-17/IL-2) of T and B-cells was observed upon in vitro antigen recall. Mapping and kinetics timeline of soluble mediator signatures for PV(D30-45) further confirmed the polyfunctional profile upon long-term in vitro culture, mediated by increased levels of IFN-γ and TNF-α along with decreased production of IL-10. These findings suggest novel insights of correlates of protection elicited by the 1/5 fractional dose of 17DD-YF vaccine.

Neutralizing antibody titers against D8 genotype and persistence of measles humoral and cell-mediated immunity eight years after the first dose of measles, mumps, and rubella vaccine in Brazilian children.

OBJECTIVE: Assess the level of measles vaccine-induced neutralizing antibodies against the D8 genotype and the persistence of humoral and cell-mediated immunity in children who received their first dose of the measles, mumps, and rubella vaccine eight years previously. METHODS: Measles-specific IgG and neutralizing antibodies were determined in serum using ELISA and plaque reduction neutralization test, respectively. Cellular response was evaluated from peripheral blood mononuclear cells (PBMC). IFN-γ-secreting cells, memory B and T cells, and immunological mediators were assayed by ELISpot, flow cytometry, and multiplex liquid microarray assay, respectively. RESULTS: Antibody concentrations declined over time; however, the vaccine-induced neutralizing antibodies' effect against D8 and vaccinal genotypes persisted. PBMC stimulated with the vaccine virus exhibited specific IFN- γ-measles-secreting responses in most participants. Participants with high levels of neutralizing antibodies showed a higher proportion of activated B cells compared to participants with low levels of neutralizing antibodies, while proportions of memory CD4+ and CD8+ T cells were similar between these groups. PBMC supernatant cytokine levels showed a significant difference between stimulated and non-stimulated conditions for IL-2, TNF-α, IL-10, and CXCL10. CONCLUSION: Despite the decline in antibody concentrations over time, the participants still demonstrated neutralizing capacity against the measles D8 genotype five to eight years after the second dose of the measles, mumps, and rubella vaccine. Additionally, most of the enrolled children exhibited cell-mediated immunity responses to measles virus stimulation.

Duration of post-vaccination humoral immunity against yellow fever in children.

INTRODUCTION: Vaccination is the most important measure for prevention and control of yellow fever. It is recommended by the World Health Organization (WHO) for residents of endemic areas and travelers to risk areas. In 2013, the WHO discontinued the recommendation of booster doses every 10 years, indicating a single dose as sufficient for lifelong protection. OBJECTIVE: Considering the lower immune response to YF vaccine in children compared to adults, this study was set out to assess the duration of immunity to YF in children vaccinated in the first two years of life. METHODS: This cross-sectional study involved children aged 9 months to 12 years with accessible vaccination records recruited in primary care units from a metropolitan area in Southeast Brazil. The serologic status (negative, indeterminate and positive), and geometric mean titers (GMT, inverse dilution) of neutralizing antibodies against YF obtained by Plaque Reduction Neutralization Test was assessed across categories of time after YF vaccination. The strength of association of seropositivity with time was assessed by the odds ratio (OR) taking recent vaccination (1-6 months) as reference. RESULTS: A total of 824 children recruited from August 2010 to July 2011were tested. The proportion of seropositivity (95% C.I.) and GMT (95% C.I.) dropped markedly across time periods: from 86.7% (80.5-91.4%), GMT 47.9 (38.3-59.9) in newly vaccinated to 59.0% (49.7-67.8%), GMT 14.8 (11.6-19.1) and 42.2% (33.8-51.0), GMT 8.6 (7.1-12.1), respectively in the subgroups vaccinated 31-72 months and 73-100 months before. CONCLUSIONS: Analogous to previous findings in adults, these data support the need for revaccination of children living in areas with yellow fever virus circulation in humans or in other primates. The data also supported the change of a booster dose to 4 years of age for those primarily vaccinated for yellow fever in the first two years of life.

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

BACKGROUND: 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.

Cytokine signatures of innate and adaptive immunity in 17DD yellow fever vaccinated children and its association with the level of neutralizing antibody.

BACKGROUND: 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-PRNT⁺ and PV-PRNT⁻), seroconverters after revaccination (RV-PRNT⁺), and unvaccinated volunteers (UV-PRNT⁻). RESULTS: The analysis demonstrated in the PV-PRNT⁺ group a balanced involvement of pro-inflammatory/regulatory adaptive immunity with a prominent participation of innate immunity pro-inflammatory events (IL-12⁺ and TNF-α⁺ NEU and MON). Using the PV-PRNT⁺ cytokine signature as a reference profile, PV-PRNT⁻ presented a striking lack of innate immunity proinflammatory response along with an increased adaptive regulatory profile (IL-4⁺CD4⁺ T cells and IL-10⁺ and IL-5⁺CD8⁺ T cells). Conversely, the RV-PRNT⁺ 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-PRNT(MEDIUM⁺), whereas a polarized regulatory response was observed in PV-PRNT⁻ and a prominent proinflammatory signature was the characteristic of PV-PRNT(HIGH⁺).