Antigen detection in vivo after immunization with different presentation forms of rabies virus antigen, II. Cellular but not humoral systemic immune responses against rabies virus immune stimulating complexes are macrophage dependent

In this paper we describe the effect of depletion of splenic macrophages on the uptake, and immune response against, different formulations of rabies virus antigen. Splenic macrophages were removed by intravenous injection with clodronate liposomes. beta-propiolacton inactivated rabies virus (RV-BPL) and immune-stimulating complexes (iscom) containing these antigens were given to macrophage-depleted and control mice. In the absence of phagocytic cells in the spleen, antigen is still trapped in the red pulp and to a lesser extent in the peri-arteriolar lymphocyte sheaths (PALS) for both antigen formulations. The localization pattern in the main area of immune response induction, namely the follicles, was unaltered after macrophage depletion. Functionally, the depletion of splenic and liver macrophages had no influence on the induction of specific antibody responses in both RV-BPL or RV-iscom immunized mice, even though the latter presentation form was clearly associated with specific localization in the marginal metallophillic macrophages. In RV-BPL immunized mice, macrophage depletion had no influence on proliferative T-cell responses. However, macrophage-depleted mice that were immunized with RV-iscom showed a significant decrease in proliferative T-cell respon

Substantially increased sensitivity of the spot-ELISA for the detection of anti-insulin antibody-secreting cells using a capture antibody and enzyme-conjugated insulin

This paper describes an antibody capture spot-ELISA for the detection of anti-insulin antibody-secreting cells. The assay is based on the binding of secreted antibodies by immobilised isotype-specific capture antibodies and subsequent detection of insulin-specific antibodies with a conjugate of human insulin and alkaline phosphatase (HI-AP). Compared with the conventional approach, using antigen for coating and employing an enzyme-linked detecting antibody, this technique improved the detection of murine cells secreting anti-insulin antibodies of different IgG subclasses

Leveraging academic knowledge in the innovation ecosystem

Scientific advancement and advancements in information technology have increased our capability for sharing information, and spreading scientific discoveries throughout society. In the past decade the Dutch government has been trying to stimulate the knowledge economy through various means. Among them the stimulation of the founding of the Dutch Centres for Entrepreneurship, and the Valorisation programme. However, over the years, publication volume has become the main indicator for being a successful scientist. This focus on publications and research disincentivizes scientists from activities that generate more concrete value for society. The Societal Impact Value Cycle seeks to offer scientists and others a toolbox for visualising and understanding the way innovation can be fostered, and how other processes can foster scientific research in return. It also maps the way by which an innovation ecosystem generates socio-economic value from academic activities. It should be noted that not all scientific research leads to innovations that generate value for society, and not all research is intended to change the course of events. Nonetheless, fostering cooperation between research institutes and societal stakeholders, and increasing awareness of how entrepreneurial skills and activities could not only lead to a return on investments necessary for scientific advancement, but also increase the societal impact from academic endeavours. This could benefit our society, and societies worldwide, both socially and economically. This publication will offer valuable insight and an effective toolbox for people interested in socio-economic value creation from scientific research, or, in other words, valorisation. Therewith, it lays at the heart of Stichting Maatschappij en Onderneming’s daily occupations and our close cooperation with the Erasmus University Rotterdam

Food-pharma convergence in medical nutrition

At present, industries within the health and life science sector are moving towards one another resulting in new industries such as the medical nutrition industry. Medical nutrition products are specific nutritional compositions for intervention in disease progression and symptom alleviation. Industry convergence, described as the blurring of boundaries between industries, plays a crucial role in the shaping of new markets and industries. Assuming that the medical nutrition industry has emerged from the convergence between the food and pharma industries, it is crucial to research how and which distinct industry domains have contributed to establish this relatively new industry. The first two stages of industry convergence (knowledge diffusion and consolidation) are measured by means of patent analysis. First, the extent of knowledge diffusion within the medical nutrition industry is graphed in a patent citation interrelations network. Subsequently the consolidation based on technological convergence

Risk in Vaccine Research and Development Quantified

To date, vaccination is the most cost-effective strategy to combat infectious diseases. Recently, a productivity gap affects the pharmaceutical industry. The productivity gap describes the situation whereby the invested resources within an industry do not match the expected product turn-over. While risk profiles (combining research and development timelines and transition rates) have been published for new chemical entities (NCE), little is documented on vaccine development. The objective is to calculate risk profiles for vaccines targeting human infectious diseases. A database was actively compiled to include all vaccine projects in development from 1998 to 2009 in the pre-clinical development phase, clinical trials phase I, II and III up to Market Registration. The average vaccine, taken from the preclinical phase, requires a development timeline of 10.71 years and has a market entry probability of 6%. Stratification by disease area reveals pandemic influenza vaccine targets as lucrative. Furthermore, vaccines targeting acute infectious diseases and prophylactic vaccines have shown to have a lower risk profile when compared to vaccines targeting chronic infections and therapeutic applications. In conclusion; these statistics apply to vaccines targeting human infectious diseases. Vaccines targeting cancer, allergy and autoimmune diseases require further analysis. Additionally, this paper does not address orphan vaccines targeting unmet medical needs, whether projects are in-licensed or self-originated and firm size and experience. Therefore, it remains to be investigated how these - and other - variables influence the vaccine risk profile. Although we find huge differences

Probiotic and synbiotic safety in infants under two years of age

In this study, we systematically evaluated safety aspects in clinical trials with probiotics and synbiotics in young infants (0-2 years of age). This study is an update of earlier reports and covers the recent literature from 2008-2013. The safety evaluation is performed along the Common Terminology Clinical Adverse Events (CTCAE) version 4.0 scale, hereby also providing guidance for future studies. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. The results show a deficiency in the precise reporting and classification of adverse events in most studies. Analysis of 57 clinical trials with probiotics and synbiotics in combination with eight follow-up studies indicate that probiotic administration to infants between 0 and 24 months is safe with regard to the evaluated strains in infants with a particular health status or susceptibility. Most adverse events and serious adverse events were considered unrelated to the study product, and there were no major safety concerns. Almost all studies concluded that none of the adverse effects were related to the study product; the study products are generally well tolerated. Finally, inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes, greatly limit the generalizability of conclusions and argue convincingly for obligatory and standardised behaviour on adverse events (CTCAE) reporting in 'food' studies

Growth phase of orally administered Lactobacillus strains differentially affects IgG1/IgG2a ratio for soluble antigens: Implications for vaccine development

Lactobacillus strains with probiotic activity are major constituents of numerous common food products. Due to their 'generally regarded as safe'-status (GRAS-status), Lactobacillus strains can also be genetically engineered for use in oral immunotherapeutic applications, such as vaccination and T lymphocyte tolerance induction in autoimmune disease. In the current study, we demonstrate that the growth phase of orally administered individual Lactobacillus strains can differentially affect antigen-specific antibody subclasses IgG1 and IgG2a, which might reflect skewing of systemic activity of T helper cell type 2 (Th2) and T helper cell type 1 (Th1) pathways, respectively. Mice were orally fed different wild type Lactobacillus strains in log phase or stationary phase and immunized intraperitoneally with a T-cell dependent protein antigen. Sera were evaluated for the ratio of antigen-specific IgG1 and IgG2a antibodies. Stationary Lactobacillus murines and Lactobacillus casei cultures, but not two other Lactobacillus strains, evoked significantly higher IgG1/IgG2a ratios than log phase cultures, possibly relating to increased activity of the Th2-pathway. Despite normal variation in antibody responses against TNP-CGG among individual mice, a high correlation was found between the IgG1 and IgG2a responses of mice within experimental groups. This differential antibody response is likely due to growth phase-dependent differences in bacterial cell composition. Since Lactobacillus growth phase dependent skewing of antibody responses possibly reflecting T-cell pathways can inadvertently affect allergic and (auto)-immune responses, the current findings strongly caution against unidimensional views on the oral administration of individual Lactobacillus strains for probiotic or immunotherapeutic purposes, but also suggest additional possibilities for immune modulation

Safety of probiotics and synbiotics in children under 18 years of age

This study aimed to systematically evaluate safety of probiotics and synbiotics in children ageing 0-18 years. This study is the third and final part in a safety trilogy and an update is provided using the most recent available clinical data (2008-2013) by means of the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 74 clinical studies indicated that probiotic and/or synbiotic administration in children is safe with regard to the specific evaluated strains, dosages and duration. The population of children include healthy, immune compromised and obese subjects, as well as subjects with intestinal disorders, infections and inflammatory disorders. This study revealed no major safety concerns, as the adverse events (AEs) were unrelated, or not suspected to be related, to the probiotic or synbiotic product. In general the study products were well tolerated. Overall, AEs occurred more frequent in the control arm compared to children receiving probiotics and/or synbiotics. Furthermore, the results indicate inadequate reporting and classification of AEs in the majority of the studies. In addition, generalizability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes

Immune activation in prolonged cART-suppressed HIV patients is comparable to that of healthy controls

Sustained immune activation during chronic HIV infection is considered to augment co-morbidity and mortality. Effective combination antiretroviral therapy (cART) has shown to dampen immune activation especially during the first year cART, but the effects of long-term cART in patients without major comorbidities remains under-investigated. We performed a comprehensive analysis including cellular, intracellular and plasma biomarkers to study the effect of cART on immune parameters in 5 groups of 10 HIV patients. All patients were without major co-morbidities and grouped based on cART duration (0, 1, 3, 5, and 10 years). We included 10 matched healthy controls for comparison. Our data show that after the first year of cART, no additional effect on the level of inflammatory markers is observed in HIV infected patients without major co morbidities. Residual immune activation status in well-treated HIV-infection is similar to levels observed in healthy controls

A critical appreciation of intangible resources in PharmaNutrition

Background: Organizations in knowledge-intensive industries such as the field of PharmaNutrition benefit from a critical consideration of intangible resources for innovation performance and competitive advantage. Effective management of these resources, however, is complicated due to difficulties in their identification, appropriation, application, and evaluation. As a consequence, knowledge-intensive organizations are at risk of suboptimal exploitation of their most important value drivers. Methods: The literature on organizational intangible resources was reviewed as part of an ongoing investigation into effective management of intangible resources in the PharmaNutrition-specific context. Results: Although high-level dimensions of intangible resources are recognized across industries, the identity and relevance of various lower-level components are heterogenous and dependent on organization's unique situational attributes. Despite the existence of historical, industry-sourced tick-the-box lists presented here, an analysis of industry-specific characteristics of intangible resources and mechanisms to appropriate their value is warranted to enable practitioners to innovate effectively and efficiently. Conclusions: This editorial aims to put the topics of intangible resources and their appropriability on the agenda, and invites scholars and practitioners to contribute to the advancement of our understanding regarding these topics through an online survey