Dengue Virus Activates Polyreactive, Natural IgG B Cells after Primary and Secondary Infection

BACKGROUND: Dengue virus is transmitted by mosquitoes and has four serotypes. Cross-protection to other serotypes lasting for a few months is observed following infection with one serotype. There is evidence that low-affinity T and/or B cells from primary infections contribute to the severe syndromes often associated with secondary dengue infections. such pronounced immune-mediated enhancement suggests a dengue-specific pattern of immune cell activation. This study investigates the acute and early convalescent B cell response leading to the generation of cross-reactive and neutralizing antibodies following dengue infection. METHODOLOGY/PRINCIPAL FINDINGS: We assayed blood samples taken from dengue patients with primary or secondary infection during acute disease and convalescence and compared them to samples from patients presenting with non-dengue related fever. Dengue induced massive early plasmablast formation, which correlated with the appearance of polyclonal, cross-reactive IgG for both primary and secondary infection. Surprisingly, the contribution of IgG to the neutralizing titer 4-7 days after fever onset was more than 50% even after primary infection. CONCLUSIONS/SIGNIFICANCE: Poly-reactive and virus serotype cross-reactive IgG are an important component of the innate response in humans during both primary and secondary dengue infection, and "innate specificities" seem to constitute part of the adaptive response in dengue. While of potential importance for protection during secondary infection, cross-reactive B cells will also compete with highly neutralizing B cells and possibly interfere with their development

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml−1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Abstract We evaluated a novel alemtuzumab-based conditioning regimen in HSCT for acquired severe aplastic anemia (SAA). In a multicenter retrospective study, 50 patients received transplants from matched sibling donors (MSD; n = 21) and unrelated donors (UD; n = 29), using fludarabine 30 mg/m2 for 4 days, cyclophosphamide 300 mg/m2 for 4 days, and alemtuzumab median total dose of 60 mg (range:40-100 mg). Median age was 35 years (range 8-62). Overall survival at 2 years was 95% ± 5% for MSD and 83% for UD HSCT (p 0.34). Cumulative incidence of graft failure was 9.5% for MSD and 14.5% for UD HSCT. Full-donor chimerism (FDC) in unfractionated peripheral blood was 42%; no patient achieved CD3 FDC. Acute GVHD was observed in only 13.5% patients (all grade I-II) and only 2 patients (4%) developed chronic GVHD. A low incidence of viral infections was seen. Factors influencing overall survival were HSCT comorbidity 2-year index (92% with score 0-1 vs 42% with score ≥ 2, P &lt; .001) and age (92% for age &lt; 50 years vs 71% ≥ 50 years, P &lt; .001). Our data suggest that the use of an alemtuzumab-based HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD.</jats:p

Second allogeneic stem cell transplant for aplastic anaemia: a retrospective study by the Severe Aplastic Anaemia Working Party of the European Society for Blood and Marrow Transplantation

We analysed the outcome of a second allogeneic haematopoietic stem cell transplant (alloHSCT) in 162 patients reported to the European Society for Blood and Marrow Transplantation between 1998 and 2009. Donor origin was a sibling in 110 and an unrelated donor in 52 transplants, respectively. The stem cell source was bone marrow in 31% and peripheral blood in 69% of transplants. The same donor as for the first alloHSCT was used in 81% of transplants whereas a change in the choice of stem cell source was reported in 56% of patients, mainly from bone marrow to peripheral blood. Neutrophil and platelet engraftment occurred in 85% and 72% of patients, after a median time of 15 and 17\ua0days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD occurred in 21% and 37% of patients, respectively. Graft failure (GF) occurred in 42 patients (26%). After a median follow-up of 3\ub75\ua0years, the 5-year overall survival (OS) was 60\ub77%. In multivariate analysis, the only factor significantly associated with a better outcome was a Karnofsky/Lansky score 6580 (higher OS). We conclude that a second alloHSCT is feasible rescue option for GF in SAA, with a successful outcome in 60% of cases

Polyclonal B cell activation after dengue infection.

<p>Fresh blood samples of dengue and control fever patients were analyzed by flow cytometry at 1–3, 4–7 and 15–25 days after onset of fever. A) CD19⁺CD20⁻CD27⁺CD138⁻ plasmablasts and CD27⁺CD138⁺ plasma cells (B) as % of lymphocytes. squares: other febrile illness (OFI), triangles: primary or secondary dengue infection. Each symbol represents one patient, lines indicate the mean. A Mann-Whitney test was used for statistical analysis. C) Gating strategy for plasmacells and plasmablasts. One secondary dengue patient with high plasma blast formation is shown. Blood was taken 3, 4 and 20 days after onset of fever.</p

Rapid induction of cross-reactive IgG antibodies after dengue infection.

<p>Longitudinal plasma samples of dengue patients were tested by ELISA for dengue-specific IgM (A) and IgG antibodies (B). A and B) Four plasma dilutions from 1∶200 to 1∶25'000 were measured to exclude non-specific binding. For the combined illustration of all samples that were analysed the OD450 of one dilution (1∶5000 for IgG and 1∶1000 for IgM) was divided by the OD450 of a standard serum that was included on each plate. Time points: 1 = 1–3 days after fever, 2 = 4–7 days after fever, 3 = 15–25 days after fever. The same patient samples were analyzed for DENV1–4. Binding intensity correlated for all four serotypes, i.e. high binding to DENV1 would also apply to DENV2, 3 and 4. Primary versus secondary infection status was confirmed with the commercially available Panbio ELISA kit (Inverness Medical, Australia). The experiment was repeated for selected samples, confirming the original results. C) Concentrations of BAFF were measured in the plasma of dengue and flu patients at the indicated time points. D) moDCs were infected with DENV, heat-inactivated (HI) DENV, polyI:C or medium and BAFF was measured in the supernatant at different time points after infection. Data are presented as % of medium control and are the means±SEM of two independent experiments, done in triplicates. TSV01∶medium compared to polyIC∶medium is significantly different (p>0.05, Two-way ANOVA). The source of BAFF in DENV-infected patients is therefore unlikely to be DCs.</p