Matrix-M™ adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine

Background: Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal. Methods: To assess the immune potentiating properties of Matrix-M (TM), mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M (TM). Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M (TM) broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses. Results: Matrix-M (TM) adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M (TM) adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained. Conclusion: The results of this study emphasize the promising potential of a Matrix-M (TM)-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunit

Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and α-smooth muscle actin (α-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-β. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, α-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of α-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of α-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-β. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of α-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of α-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint

Protection against H5N1 Influenza Virus Induced by Matrix-M Adjuvanted Seasonal Virosomal Vaccine in Mice Requires Both Antibodies and T Cells.

BACKGROUND:It remains important to develop the next generation of influenza vaccines that can provide protection against vaccine mismatched strains and to be prepared for potential pandemic outbreaks. To achieve this, the understanding of the immunological parameters that mediate such broad protection is crucial. METHOD:In the current study we assessed the contribution of humoral and cellular immune responses to heterosubtypic protection against H5N1 induced by a Matrix-M (MM) adjuvanted seasonal influenza vaccine by serum transfer and T-cell depletion studies. RESULTS:We demonstrate that the heterosubtypic protection against H5N1 induced by MM adjuvanted vaccine is partially mediated by antibodies. The serum contained both H5N1 cross-reactive hemagglutinin (HA)- and neuraminidase (NA)-specific antibodies but with limited virus neutralizing and no hemagglutination inhibiting activity. The cross-reactive antibodies induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting a role for the Fc part of the antibodies in protection against H5N1. Besides H5N1 specific antibody responses, cross-reactive HA- and NA-specific T-cell responses were induced by the adjuvanted vaccine. T-cell depletion experiments demonstrated that both CD4+ and CD8+ T cells contribute to protection. CONCLUSION:Our study demonstrates that cross-protection against H5N1 induced by MM adjuvanted seasonal virosomal influenza vaccine requires both the humoral and cellular arm of the immune system

Positive Effect of Large Birth Intervals on Early Childhood Hemoglobin Levels in Africa Is Limited to Girls: Cross-Sectional DHS Study

<div><p>Background</p><p>Short birth intervals are independently associated with increased risk of adverse maternal, perinatal, infant and child outcomes. Anemia in children, which is highly prevalent in Africa, is associated with an increased risk of morbidity and mortality. Birth spacing is advocated as a tool to reduce anemia in preschool African children, but the role of gender differences and contextual factors has been neglected. The present study aims to determine to what extent the length of preceding birth interval influences the hemoglobin levels of African preschool children in general, as well as for boys and girls separately, and which contextual factors thereby play a crucial role.</p><p>Methods and Findings</p><p>This cross-sectional study uses data from Demographic and Health Surveys (DHS) conducted between 2003 and 2011 in 20 African countries. All preschool children aged 6–59 months with a valid hemoglobin measurement and a preceding birth interval of 7–72 months as well as their corresponding multigravida mothers aged 21–49 years were included in the study. Hemoglobin levels of children and mothers were measured in g/l, while birth intervals were calculated as months difference between consecutive births. Multivariate analyses were done to examine the relationship between length of preceding birth interval and child hemoglobin levels, adjusted for factors at the individual, household, community, district, and country level. A positive linear relationship was observed between birth interval and the 49,260 included children’s hemoglobin level, whereby age and sex of the child, hemoglobin level of the mother, household wealth, mother’s education and urbanization of place of residence also showed positive associations. In the interaction models, the effect of a month increase in birth interval is associated with an average increase of 0.025 g/l in hemoglobin level (P = 0.001) in girls, while for boys the effect was not significant. In addition, for girls, the effect of length of preceding birth interval was highest in young mothers and mothers with higher hemoglobin levels, while for boys, the highest effect was noticed for those living in more highly educated regions. Finally, significantly higher hemoglobin levels of girls compared to boys were observed at birth but with increasing age, the sex difference in hemoglobin level gradually becomes smaller.</p><p>Conclusions</p><p>A longer birth interval has a modest positive effect on early childhood hemoglobin levels of girls, and this effect is strongest when their mothers are in their early twenties and have a high hemoglobin level. Remarkably, although the physiological iron requirement is higher for boys than girls, birth spacing has little influence on hemoglobin levels of preschool boys. We speculate that the preference for male offspring in large parts of Africa significantly influences nutritional patterns of African preschool boys and girls, and as such also determines the different effect of birth spacing. Finally, gender aspects should be considered in intervention programs that aim to improve anemia in African children.</p></div

Baseline characteristics of children (age 6–59 months) and their mothers (age 21–49 years) from 20 African countries (DHS database).

<p>Baseline characteristics of children (age 6–59 months) and their mothers (age 21–49 years) from 20 African countries (DHS database).</p

Summary of separate interaction models for boys and girls.

<p>Multivariate models for the relationship of hemoglobin level of children (age 6–59 months, n = 49,260) from 20 African countries (DHS database) and their preceding birth interval adjusted for all predictors.</p><p>* P<0.05</p><p>** P,0.01</p><p>^# P<0.0056 (Bonferroni correction)</p><p>Hb = Hemoglobin level</p><p>Summary of separate interaction models for boys and girls.</p

Bivariate and Multivariate analyses for hemoglobin level of African children (age 6–59 months, n = 49,260) from 20 African countries (DHS database).

<p>* P<0.05</p><p>** P<0.01</p><p>BMI = Body Mass Index</p><p>Bivariate and Multivariate analyses for hemoglobin level of African children (age 6–59 months, n = 49,260) from 20 African countries (DHS database).</p

Mean hemoglobin levels of mothers and children in 20 African countries.

<p>Mean hemoglobin levels of mothers and children in 20 African countries.</p