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We performed a detailed analysis of immunophenotypic features of circulating leukocytes and spleen cells from cynomolgus macaques that had been naturally infected with Trypanosoma cruzi , identifying their unique and shared characteristics in relation to cardiac histopathological lesion status. T. cruzi- infected macaques were categorized into three groups: asymptomatic [CCC(-)], with mild chronic chagasic cardiopathy [CCC(+)], or with moderate chronic chagasic cardiopathy [CCC(++)]. Our findings demonstrated significant differences in innate and adaptive immunity cells of the peripheral blood and spleen compartments, by comparison with non-infected controls. CCC(+) and CCC(++) hosts exhibited decreased frequencies of monocytes, NK and NKT-cell subsets in both compartments, and increased frequencies of activated CD8 + T-cells and GranA + /GranB + cells. While a balanced cytokine profile (TNF/IL-10) was observed in peripheral blood of CCC(-) macaques, a predominant pro-inflammatory profile (increased levels of TNF and IFN/IL-10) was observed in both CCC(+) and CCC(++) subgroups. Our data demonstrated that cardiac histopathological features of T. cruzi -infected cynomolgus macaques are associated with perturbations of the immune system similarly to those observed in chagasic humans. These results provide further support for the validity of the cynomolgus macaque model for pre-clinical research on Chagas disease, and provide insights pertaining to the underlying immunological mechanisms involved in the progression of cardiac Chagas disease.

The present study aimed to investigate whether the serum biomarkers of immune response orchestrate the seroconversion status in patients with autoimmune diseases (AID) upon planned primary 17DD-YF vaccination. For this purpose a total of 161 individuals were enrolled in a prospective study, including patients with Rheumatoid Arthritis (RA = 38), Spondyloarthritis (SpA = 51), Systemic Lupus Erythematosus (SLE = 21) and Sjögren’s Syndrome (SS = 30) along with a group of healthy controls (HC = 21). Analysis of plaque reduction neutralization test (PRNT) titers and seropositivity rates along with the 17DD-YF viremia and serum biomarkers were carried out at distinct time points (D0/D3–4/D5–6/D7/D14–28). The results demonstrated an overall lower PRNT titer and seropositivity rate (170 vs. 448; 77 vs. 95%) in AID as compared to HC, especially in SpA and SLE subgroups. No significant differences were observed in the viremia levels amongst groups. In general, a more prominent serum biomarker response was observed in AID as compared to HC, throughout the timeline kinetics. Remarkably, AID/PRNT(−) exhibited higher levels of several biomarkers at baseline as compared to AID/PRNT+. Moreover, while AID/PRNT(+) exhibited earlier increase in serum biomarkers at D3–4/D5–6, the AID/PRNT(−) displayed higher response at later time points (D7/D14–D28). Of note, a synchronic increase of IFN-γ at the peak of viremia (D5–6) was observed in HC and AID/PRNT(+) groups, whereas a later asynchronous IFN-γ response was reported for AID/PRNT(−) at D7. The biomarker profile tends to deflate at post-vaccination timeline, highlighting a putative immunomodulatory effect of live attenuated 17DD-YF vaccine in AID/PRNT(+), but not in AID/PRNT(−). Altogether these data suggested that inflammatory status prior vaccination, low IFN-γ at viremia peak and the occurrence of asynchronous biomarker storm after 17DD-YF vaccination may orchestrate the lack of neutralizing antibody response γ.

Immunobiography describes the life-long effects of exogenous or endogenous stimuli on remodeling of immune cell biology, including the development of memory T and B-cells. The present study aimed at investigating the rhythms of changes in phenotypic features of memory T and B-cells along childhood and adolescence. A descriptive-observational investigation was conducted including 812 healthy volunteers, clustered into six consecutive age groups (9 Mths –1 Yr ; 2 Yrs ; 3–4 Yrs ; 5–7 Yrs ; 8–10 Yrs ; 11–18 Yrs ). Immunophenotypic analysis of memory T-cell (CD4 + and CD8 + ) and B-cell subsets were performed by flow cytometry. The results pointed out that memory-related biomarkers of T and B-cells displayed a bimodal profile along healthy childhood and adolescence, regardless of sex. The first stage of changes occurs around 2 Yrs , with predominance of naive cells, while the second and more prominent wave occurs around the age 8–10 Yrs , with the prevalence of memory phenotypes. The neighborhood connectivity profile analysis demonstrated that the number of correlations reaches a peak at 11–18 Yrs and lower values along the childhood. Males presented higher and conserved number of correlations when compared to females. Altogether, our results provide new insights into immunobiography and a better understanding of interactions among the cellular subsets studied here during childhood and adolescence.

Severe COVID-19 is marked by profound immune dysregulation, yet the interplay between humoral and inflammatory responses that determines clinical outcomes in critically ill patients remains incompletely understood. We evaluated longitudinal antibody and soluble immune mediator profiles to identify prognostic signatures associated with survival in severe COVID-19. In this prospective longitudinal study, peripheral blood samples were collected from 30 unvaccinated adults with severe COVID-19 admitted to the intensive care unit (ICU) and 30 healthy controls. Serum concentrations of SARS-CoV-2-specific IgM, IgG and IgA antibodies (S1, RBD and N) and 27 cytokines, chemokines and growth factors were quantified at ICU admission (D0), Day 7 (D7) and Day 14 (D14) using Luminex multiplex assays. Patients were classified according to clinical outcome: discharge (DIS) or death (DEA). DIS and DEA patients exhibited distinct immunological trajectories. DEA patients showed early elevations of IgM anti-N and IgM anti-RBD at D0, accompanied by increased IFN-γ. At D7, persistently elevated TNF-α and FGF-basic differentiated nonsurvivors, while by D14, higher levels of CXCL8, CCL4, CXCL10 and G-CSF were strongly associated with mortality. In contrast, DIS patients exhibited more coordinated immune regulation, including sustained IL-13 production and higher IgA anti-S1 and IgA anti-RBD levels. Integrated humoral and inflammatory signatures, particularly early IgM anti-N/anti-RBD responses and sequential increases in IFN-γ, TNF-α, FGF-basic, CXCL8, CCL4, CXCL10 and G-CSF, highlight immune signatures associated with poor outcomes. IL-13 and coordinated antibody interactions may reflect protective immune pathways. These findings highlight the prognostic value of multidimensional immune monitoring in severe COVID-19.

Background The 17DD-yellow fever (YF) vaccine induces a long-lasting protective immunity, resulting from humoral and cellular immunological memory. The treatment of rheumatoid arthritis (RA) patients with disease-modifying anti-rheumatic drugs (DMARD) may affect pre-existing 17DD-vaccine protective immunity and increase the risk of acquiring YF infection. Our goal was to determine whether DMARD would affect the duration of YF-specific protective immunity in RA patients. Methods A total of 122 RA patients, previously immunized with the 17DD-YF vaccine (1–5, 5–9, and ≥ 10 years) and currently under DMARD therapy, were enrolled in the present investigation. Immunomodulatory therapy encompasses the use of conventional synthetic DMARD alone (csDMARD) or combines with biological DMARD (cs+bDMARD). A total of 226 healthy subjects were recruited as a control group (CONT). Neutralizing antibody responses were measured by a plaque-reduction neutralization test (PRNT), and cellular immunity was evaluated by an in vitro 17DD-YF-specific peripheral blood lymphoproliferative assay. Results The data demonstrated that csDMARD therapy did not affect the duration of protective immunity induced by the 17DD-YF vaccine compared to that of CONT, as both presented a significant time-dependent decline at 10 years after vaccination. Conversely, cs+bDMARD therapy induced a premature depletion in the main determinants of the vaccine protective response, with diminished PRNT seropositivity levels between 5 and 9 years and impaired effector memory in CD8 + T cells as early as 1–5 years after 17DD-YF vaccination. Conclusions These findings could support changing the vaccination schedule of this population, with the possibility of a planned booster dose upon the suspension of bDMARD in cases where this is allowed, even before 10 years following 17DD-YF vaccination. The benefit of a planned booster dose should be evaluated in further studies. Trial registration RBR-946bv5 . Date of registration: March 05, 2018. Retrospectively registered

The present study intended to characterize the clinical features and outcomes of SARS-CoV-2 infection at distinct pregnancy trimesters. A total of 260 pregnant women with SARS-CoV-2 infection at any pregnancy trimester were enrolled in a prospective follow-up study. Clinical features were recorded between the SARS-CoV-2 infection diagnosis towards delivery and postpartum period. ANOVA and Chi-square/Fisher tests, Bi- and multivariate analyses were performed to verify the effect of predictors on disease outcome, adjusted for the pregestational variables. Data demonstrated that anosmia (64.6%), nasal congestion/discharge (61.5%), headache (60.8%), ageusia (58.5%) and myalgia (58.5%) were the most common symptoms observed amongst pregnant women with non-severe COVID-19. Fever (44.6%) and dyspnea (36.5%) were associated with higher disease severity. Gestational diabetes mellitus (35.8%), systemic arterial hypertension (18.1%), preterm delivery (11.5%) and superimposed preeclampsia (6.2%) were reported as adverse pregnancy outcomes amongst pregnant women with COVID-19. Parturients with acute COVID-19 and pregnant women infected at the 3 rd trimester presented more severe or critical outcomes as compared to those infected at 2 nd and 1 st trimesters. Preterm labor (Odds Ratio = 3.64), acute fetal distress (Prevalence Ratio = 2.40) and Apgar 1 st minute score ≤ 7 (Prevalence Ratio = 2.56) were adverse outcomes reported in parturients with acute COVID-19 and those with severe or critical outcomes. Together these findings demonstrated that SARS-CoV-2 infection during pregnancy was associated with relevant maternal and neonatal adverse outcomes. The understanding of the clinical and obstetric outcomes of COVID-19 during pregnancy can provide insights to establish the most suitable approach for clinical management of pregnant women.

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, imposing the need for periodic booster doses. However, whether booster doses should be applied to the entire population or groups, and the booster doses interval, remains unclear. In this study, we evaluated humoral reactivity kinetics from before the first dose to 180 days after the third booster dose in different schedules in a well-controlled health worker cohort. Among the 2,506 employees, the first 500 vaccinated health workers were invited to participate. The third booster dose was administered 8 months after the first dose. Among the invited participants, 470 were included in the study; 258 received inactivated vaccine CoronaVac (VAC group) and 212 received viral vector vaccine ChAdOx1 (AZV group). The groups were homogeneous in terms of age and sex. 347 participants were followed up after the booster dose with AZV or BNT162b2 (Pfizer, BNT group): 63 with VAC/AZV, 117 with VAC/BNT, 72 with the AZV/AZV and 95 with AZV/BNT schedules. Blood samples were collected immediately before, 28 days after each dose and 180 days after the primary vaccination and booster dose. Anti-SARS-CoV-2 antibodies were measured by chemiluminescence and plaque reduction neutralization test (PRNT). Plasma immune mediators were quantified using a multiplex immunoassay. Geometric mean of antibodies increased 28 days after the second dose with 100 % seroconversion rate in both groups and decreased 180 days after the first dose. In the baseline-seropositive VAC group, the levels of plasma immune mediators increased after the second dose. Booster dose was applied at 4–6 months after the primary vaccination. Heterologous booster in VAC or AZV primary vaccinees were effective maintaining the titers of anti-SARS-CoV-2 antibodies even after 6 months of follow-up. The heterologous schedule induced higher and stable antibody reactivity, even after 180 days, protecting to ancestral (Wuhan), Delta, and Omicron variants.

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.

Introduction The present study aimed at evaluating the systemic profile and network connectivity of immune mediators during acute chikungunya fever (CHIKF) according to days of symptoms onset and ageing. Methods A total of 161 volunteers (76 CHIKF patients and 85 non-infected healthy controls) were enrolled. Results and discussion Data demonstrated that a massive and polyfunctional storm of serum immune mediators was observed in CHIKF. Distinct patterns of mediators were observed according to days of symptoms onset. Most chemokines and proinflammatory cytokines were increased early at D0-1, with some increased throughout the kinetics timeline, while others presented a waning profile towards D4-12. Rhythmic signatures further underscored these findings. Increased levels IL-17 appeared as a hallmark of intense arthralgia, while CCL5&IL-5 and TNF-α&IL-10 duets are age-tunning features in CHIKF. Differential connectivity of networks was observed with ageing, with a progressive increase in the overall connectivity from < 8 yo towards 51–89 yo. Of note, subsets of immune mediators (IL-17, IL-2 and IL-5) displayed hotspots of hyperconnectivity in elderly as compared to younger patients. Conclusion Together, the overall scenario reveals unique patterns of soluble immune mediators during acute CHIKF infection with an oscillating symphony according to days of symptoms and ageing, which brings insight to future tailor-made therapeutic interventions.

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.