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Influenza vaccination is central to reducing morbidity and mortality. However, vaccine-induced immune responses vary considerably across vaccine platforms. Hemagglutination inhibition (HAI) titers are widely used as correlates of protection, but do not fully capture the complexity of memory B-cell (MBC) responses. This study employed an integrated analysis of humoral and MBC responses elicited by three licensed influenza vaccines: inactivated Fluzone standard dose (FluZ), recombinant protein-based FluBlok (FluB), and live-attenuated intranasal FluMist (FluM). FluB-vaccinees had the most robust HAI and MBC responses, with increased frequencies of switched memory and IgG memory across all HA components (H1, H3, and IBV), along with increased IgA resting memory and IgG activated memory to H1 and H3, and IgG resting memory to H1 and IBV. FluZ-vaccinees had robust, but comparatively lower responses, including increased IgG memory to H1 and IBV, but reduced switched memory compared to FluB-vaccinees. FluM-vaccinees had the lowest HAI titers but increased unswitched memory and IgA memory to H1 and IBV, along with higher IgM memory to H3. Notably, FluM-vaccinees showed greater inter-correlation among multiple MBC subsets, particularly for H3. These findings uncover distinct platform-specific immune landscape and demonstrate that FluB induces superior MBC responses, providing a framework for designing next-generation vaccines.

This investigation elucidated the differences in humoral and H1N1 HA-specific memory B-cells response in participants exhibiting distinct immune response patterns prior to and after vaccination with Fluzone, the quadrivalent split-inactivated seasonal influenza virus vaccine. Participants were categorized into persistent non-responders and persistent responders based on their hemagglutination-inhibition (HAI) antibody titers to the H1N1 component from each vaccine administered between the 2019-2020 to 2023-2024 seasons. Persistent responders had higher fold change in H1N1 HA-specific CD21 expressing B-cells, plasmablasts, and plasma cells. A significant increase in H1N1 HA-specific transitional B-cells in persistent non-responders was observed. The frequency and fold change of H1N1-specific IgM-expressing memory B-cells was higher in persistent non-responders. Dimensionality reduction analysis also demonstrated higher IgM expression for persistent non-responders than persistent responders. Furthermore, persistent non-responders had a significant fold change increase in IgA tissue-like memory, IgG exhausted tissue-like memory, and double negative (DN) activated memory cells. In contrast, persistent responders had increased frequency of IgG-activated memory B-cells, IgG resting B-cells and DN resting B-cells. Correlation analysis revealed a positive correlation between HAI titers and DN memory B-cells and a negative correlation between HAI titers and IgG-expressing memory B-cells in persistent non-responders. Conversely, persistent responders had a positive correlation between HAI titers and IgA resting memory B-cells and a negative correlation between IgG memory B-cells and DN memory B-cells. Overall, this study provided valuable insights into the differential immune memory B-cell responses following influenza virus vaccination and paves the way for future research to further unravel the complexities of vaccine-induced memory B-cells and ultimately improve vaccination strategies against influenza virus infection.

The present investigation comprised two independent observational arms to evaluate the influence of pre-existing flavivirus humoral immunity and the age-impact on 17DD-YF vaccination immunity. Flavivirus (YFV; DENV; ZIKV) serology and YF-specific cellular immunity was evaluated in 288 children/9Mths–4Yrs and 288 adults/18–49Yrs residents of areas without YFV circulation. Data demonstrated that flavivirus seropositivity at baseline was higher in Adults as compared to Children (26%;87%;67% vs 6%;13%;15%, respectively). The heterologous flavivirus seropositivity (DENV; ZIKV) did not impact the YF-specific cellular immune response at baseline. However, higher levels of NCD4, EMCD8, IFN-MCD8, NCD19 and nCMCD19 were observed in subjects with pre-existing YFV seropositivity. Primary vaccination of YFV-seronegative volunteers led to higher levels of YF-neutralizing antibodies in Adults as compared to Younger Children (9Mths–2Yrs). Although similar seropositivity rates observed amongst Children and Adults at D30-45, lower rates were observed in Younger Children (9Mths–2Yrs) at D365 (94%;95%;100% vs 87%;96%;99%, respectively). A progressive decline in antibody levels were reported at D365, being more expressive in Children as compared to Adults. All age-subgroups exhibited at D30-45 increased levels of eEfCD4, EMCD4, IFN-MCD8 and nCMCD19 together with a decrease of eEfCD8 and CMCD8. While an increase of EMCD8 were observed in all subgroups at D30-45, a declined duration at D365 was reported only in Younger Children (9Mths–2Yrs). Biomarker signatures further support that only Younger Children (9Mths–2Yrs) presented a progressive decline of EMCD8 at D365. Together, these findings demonstrated that regardless the similarities observed in YF-neutralizing antibodies, the age impacts the duration of cellular immune response to primary 17DD-YF vaccination.

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) (532 vs 398). 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.

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.

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 ( = 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.

The present study aimed to evaluate the kinetics of the phenotypic profile and integrative networks of T/B-cells in severe COVID-19 patients, categorized according to disease outcome, during the circulation of the B.1.1.28 and B.1.1.33 SARS-CoV-2 strains in Brazil. Peripheral blood obtained at distinct time points (baseline/D0; D7; D14-28) was used for ex vivo flow cytometry immunophenotyping. The data demonstrated a decrease at D0 in the frequency of CD3+ T-cells and CD4+ T-cells and an increase in B-cells with mixed activation/exhaustion profiles. Higher changes in B-cell and CD4+ T-cells at D7 were associated with discharge/death outcomes, respectively. Regardless of the lower T/B-cell connectivity at D0, distinct profiles from D7/D14-28 revealed that, while discharge was associated with increasing connectivity for B-cells, CD4+ and CD8+ T-cells death was related to increased connectivity involving B-cells, but with lower connections mediated by CD4+ T-cells. The CD4+CD38+ and CD8+CD69+ subsets accurately classified COVID-19 vs. healthy controls throughout the kinetic analysis. Binary logistic regression identified CD4+CD107a+, CD4+T-bet+, CD8+CD69+, and CD8+T-bet+ at D0 and CD4+CD45RO+CD27+ at D7 as subsets associated with disease outcomes. Results showed that distinct phenotypic timeline kinetics and integrative networks of T/B-cells are associated with COVID-19 outcomes that may subsidize the establishment of applicable biomarkers for clinical/therapeutic monitoring.

[This corrects the article DOI: 10.3389/fimmu.2019.01211.].

Fractional dose is an important strategy to increase access to vaccines. This study evaluated the effectiveness, safety, and immunogenicity of half dose of ChAdOx1 nCoV-19 vaccine. A non-inferiority non-randomized controlled trial compared a half dose of ChAdOx1 nCoV-19 with the full dose, with an interval of 8 to 10 weeks, in individuals aged 18–49 years. The primary endpoints were the incidence rate of new cases/1,000 person-year at 90 days after 14 days of the second dose, confirmed by RT-PCR and new cases registered at SUS National Health Surveillance Database (e-SUS VS). The anti-SARS-CoV-2 spike (S) protein receptor binding domain (RBD) by chemiluminescence and the neutralizing antibodies by plaque reduction neutralization test (PRNT) were titrated. The soluble biomarkers were quantified with a multiplex immunoassay. Follow-up was 90 days after 14 days of the second dose. A total of 29,598 individuals were vaccinated. After exclusion, 16,570 individuals who received half a dose and 6,402 who received full doses were analyzed. The incidence of new cases confirmed by RT-PCR of half dose was non-inferior to full dose (23.7 vs. 25.7 cases per 1,000 persons-year [coefficient group -0.09 CI95%(-0.49 to 0.31)], even after adjusting for age and sex. There were no deaths or hospitalization after immunization of either group. Immunogenicity was evaluated in a subsample (N=558) compared to 154 healthcare workers who received a full dose. The seroconversion rate in seronegative individuals at baseline half dose was 99.8%, similar to that of the full dose (100%). Geometric mean concentration (95% CI; BAU/mL) were half dose = 188 (163-217) and full dose = 529 (423–663) (p < 0.001). In seropositive subjects at baseline (pre-immune individuals), the first dose induced very high and similar IgG-S in half dose 1,359 (1,245-1,483) and full dose 1,354 (1,048–1,749) BAU/mL. A half dose induced a high increase in plasma chemokines, pro-inflammatory/regulatory cytokines, and growth factors. The frequency of adverse events was similar. No serious adverse events or deaths were reported. A half dose of ChAdOx1 nCoV-19 is as effective, safe, and immunogenic as the full dose. The immune response in pre-immune (seropositive in the baseline) individuals indicates that the half dose may be a booster dose schedule.

It has been demonstrated that the implementation of rapid response teams (RRT) may improve clinical outcomes. Nevertheless, predictors of mortality among patients admitted to the intensive care unit (ICU) or to the step-down unit (SDU) after a RRT activation are not fully understood. To describe clinical characteristics, resource use, main outcomes, and to address predictors of in-hospital mortality among patients admitted to the ICU/SDU after RRT activation. Retrospective single-center cohort study conducted in a medical-surgical ICU/SDU located in a private quaternary care hospital. Adult patients admitted to the ICU or SDU between 2012 and 2020 were compared according to in-hospital mortality. A multivariate logistic regression analysis was performed to identify independent predictors of in-hospital mortality. Among the 3841 patients included in this analysis [3165 (82.4%) survivors and 676 (17.6%) non-survivors], 1972 (51.3%) were admitted to the ICU and 1869 (48.7%) were admitted to the SDU. Compared to survivors, non-survivors were older [76 (64-87) yrs. vs. 67 (50-81) yrs.; p < 0.001], had a higher SAPS 3 score [64 (56-72) vs. 49 (40-57); p < 0.001], and had a longer length of stay (LOS) before unit admission [8 (3-19) days vs. 2 (1-7) days; p < 0.001). Non-survivors used more non-invasive ventilation (NIV) (42.2% vs. 20.9%; p < 0.001), mechanical ventilation (MV) (36.7% vs. 9.3%; p < 0.001), vasopressors (39.2% vs. 12.3%; p < 0.001), renal replacement therapy (15.5% vs. 4.3%; p < 0.001), and blood components transfusion (34.9% vs. 14.0%; p < 0.001). Independent predictors of in-hospital mortality were the SAPS 3 score, the Charlson Comorbidity Index, LOS before unit admission, immunosuppression, respiratory rate < 8 or > 28 ipm criteria for RRT activation, RRT activation during the night shift, and the need for high-flow nasal cannula, NIV, MV, vasopressors, and blood components transfusion. Multiple factors may affect outcomes of ICU/SDU-admitted patients after RRT activation. Therefore, efforts should be made to boost RRT effectiveness to improve patient safety.