Kristoffer Jarlov Jensen

Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

Background.u2003Bacillus Calmette–Guérin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. Methods.u2003Within a randomized trial in LBW infants in Guinea-Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4 or -7/8, or purified protein derivative (PPD). Results.u2003Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ. Conclusion.u2003Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro-inflammatory cytokines. BCG may accelerate the development of the neonatal immune system, mediating comprehensive protection against infections and mortality.

An enigma: why vitamin A supplementation does not always reduce mortality even though vitamin A deficiency is associated with increased mortality

Background: Vitamin A deficiency (VAD) is associated with increased mortality. To prevent VAD, WHO recommends high-dose vitamin A supplementation (VAS) every 4–6 months for children aged between 6 months and 5 years of age in countries at risk of VAD. The policy is based on randomized clinical trials (RCTs) conducted in the late 1980s and early 1990s. Recent RCTs indicate that the policy may have ceased to be beneficial. In addition, RCTs attempting to extend the benefits to younger children have yielded conflicting results. Stratified analyses suggest that whereas some subgroups benefit more than expected from VAS, other subgroups may experience negative effects. Methods and Results: We reviewed the potential modifiers of the effect of VAS. The variable effect of VAS was not explained by underlying differences in VAD. Rather, the effect may depend on the sex of the child, the vaccine status and previous supplementation with vitamin A. Vitamin A is known to affect the Th1/Th2 balance and, in addition, recent evidence suggests that vitamin A may also induce epigenetic changes leading to down-regulation of the innate immune response. Thus VAS protects against VAD but has also important and long-lasting immunological effects, and the effect of providing VAS may vary depending on the state of the immune system. Conclusions: To design optimal VAS programmes which target those who benefit and avoid those harmed, more studies are needed. Work is ongoing to define whether neonatal VAS should be considered in subgroups. In the most recent RCT in older children, VAS doubled the mortality for males but halved mortality for females. Hence, we urgently need to re-assess the effect of VAS on older children in large-scale RCTs powered to study effect modification by sex and other potential effect modifiers, and with nested immunological studies.

Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial

INTRODUCTIONnBacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual delayed BCG, the manufacturer of the BCG vaccine experienced a period with relatively slow growth rate of the BCG. We investigated the association between growth rate of BCG when manufacturing the vaccine and its capability to induce immune responses in vivo and in vitro.nnnMETHODSn1633 neonates were randomised to BCG at birth and examined for scar at 12 months; a subgroup was tested for PPD response at 2 and 6 months. The BCG batches from the Slow growth period were compared with the precedent and subsequent Normal growth batches with regard to prevalence and size of BCG scar and PPD response. We also tested the effect of batches on in vitro cytokine responses.nnnRESULTSnAt 12 months, the Slow growth batches were associated with higher BCG scar prevalence (98.2%) than the precedent batches (92.3%, p=0.01) but the prevalence remained high after return to normal growth (98.8%, p=0.52). The Slow growth batches were associated with larger scar size (5.0mm) than precedent (4.4mm, p<0.01) and subsequent batches (4.8mm, p=0.03). Compared with Normal growth batches, the Slow growth batches were associated with a higher prevalence of positive PPD responses, and among PPD positive children, a larger PPD reaction (geometric mean ratio: 1.40 (1.20-1.63)) at 2 months. In response to secondary heterologous stimulation, monocytes primed with Slow growth batches induced higher IL-6 (p=0.03) and TNF-α responses (p=0.03) compared with Normal growth batches.nnnCONCLUSIONnThe study indicates that variations in the production of BCG vaccine may influence important immunological effects of the vaccine.nnnTRIAL REGISTRATIONnclinicaltrials.gov (NCT00625482).

Heterologous and sex differential effects of administering vitamin A supplementation with vaccines

WHO recommends high-dose vitamin A supplementation (VAS) to children from 6 months to 5 years of age in low-income countries, in order to prevent and treat vitamin A deficiency-associated morbidity and mortality. The current policy does not discriminate this recommendation either by sex or vaccination status of the child. There is accumulating evidence that the effects of VAS on morbidity, mortality and immunological parameters depend on concomitant vaccination status. Moreover, these interactions may manifest differently in males and females. Certain vaccines administered through the Expanded Program on Immunization have been shown to alter all-cause mortality from infections other than the vaccine-targeted disease. This review summarizes the evidence from observational studies and randomized-controlled trials of the effects of VAS on these so-called heterologous or non-specific effects of vaccines, with a focus on sex differences. In general, VAS seems to enhance the heterologous effects of vaccines, particularly for diphtheria-tetanus-pertussis and live measles vaccines, where some studies, although not unanimously, show a stronger interaction between VAS and vaccination in females. We suggest that vaccination status and sex should be considered when evaluating the effects of VAS in early life.

Appropriate reactions to globalisation? Interest group theory and trade associations in clothing between 1970 and 2000 -- a comparison between Denmark and Sweden

Today both Denmark and Sweden are successful fashion exporters due to the re-export of clothing designed in Scandinavia and produced in low-wage countries, while domestic clothing manufacturing has become almost non-existent over the past 20 years. This article compares the strategies of Danish and Swedish trade associations in clothing manufacturing and discusses whether or not the associations encouraged the abandonment of local manufacturing and adoption of global value chains. The analysis is carried out on the basis of interest group theory as developed by Mancur Olson and others, and the findings confirm that interest group influence can entail long-term negative effects, but also that variations in institutional settings are decisive.

Assessment of HIV-1 Patient Recruitability in the Republic of Guinea-Bissau Using African versus North American Hematology and Biochemistry Reference Intervals

ABSTRACT Hematology and biochemistry reference intervals have been derived from healthy, HIV-negative populations to guide clinical trials worldwide. However, it is less clear how such values may be applied to clinical trials involving HIV-infected individuals. We show that contradictory interpretations about patient recruitability are reached when applying African versus North American reference intervals to an HIV-1 cohort in Guinea-Bissau. These observations underscore the need to question non-African guidelines in the context of HIV intervention clinical trials in Africa.

Clade A HIV-1 Gag-specific T cell responses are frequent but do not correlate with viral loads in a cohort of treatment-naïve HIV-infected individuals living in Guinea-Bissau.

In a phase I clinical trial in Guinea-Bissau, we have tested an immunotherapeutic HIV-1 vaccine candidate in HIV-1-infected subjects (V. R. Gomez Roman, K. J. Jensen, S. S. Jensen, C. Leo-Hansen, S. Jespersen, D. S. Te, C. M. Rodrigues, C. M. Janitzek, L. Vinner, T. L. Katzenstein, P. Andersen, I

Successful strategy leading to lock-in – lessons from the Danish garment industry, 1960 to 2000

Abstract The article analyses the development of two prominent Danish clothing producers in the years after 1960, Tage Vanggaards dressmaking factory and the slacks manufacturer Brandtex, during which period each had their success despite the general trend within the industry. The article has as its point of departure an evaluation of the companies strategies and the difficulties they encountered when the need arose for strategic change. It concludes that both companies got caught in what we might call a strategic paradox: their success was the result of a willingness to maintain the same strategy for about 20 years, but the problems they encountered following these years (an inability to see the world differently) was the result of the same willingness. It is argued that a key to understanding the lock-in that happened could be found in the narratives that evolved inside and around the companies.

The non-globalisation of modern food retailing: the case of the failed Coop Norden merger

ABSTRACT By discussing the creation and subsequent failure of Coop Norden, set up by the Scandinavian consumer co-operatives in 2002 as a common wholesale and food retail enterprise, this article provides insights into the nature of the Scandinavian food retail sector and co-operative enterprises in an era of globalisation. The article combines recent research on the globalisation of retailing with the academic literature on the economic position and development of consumer co-operative enterprises. The article concludes that the failure of Coop Norden can be seen as the natural consequence of two inherent problems: 1. A flawed vision among co-operative managers on how globalisation would impact retailing and 2. A misalignment between Danish, Norwegian and Swedish co-operative agendas. The article is based on comprehensive studies of the internal co-operative archives in Denmark and Norway.

Seasonal and sex-specific variations in haematological parameters in 4 to 5.5-month-old infants in Guinea-Bissau, West Africa

Abstract Objective This study investigated seasonal and sex-specific variations in the haematological parameters and established reference ranges for these parameters in healthy 4 to 5.5-month-old infants in Guinea-Bissau. Methods Within a randomised trial of early measles vaccination, over a period of 13 months blood samples were collected from infants aged 4 to 5.5 months. Haematological parameters were determined by an automated cell counter and compared in linear regression models providing geometric mean ratios (GMR). Results Blood samples from 501 infants (n=248 boys, 49.5%) were obtained, and 285 (56.9%) were collected in the rainy season. Median age was 4.7 months (range 3.7 to 7.2 months). Eosinophil and platelet counts were lower in the dry season (December to May) than in the rainy season (GMR 0.79 [95% CI 0.68–0.92]) and 0.93 [0.87–1.00], respectively). The calculated reference ranges were wider and generally higher than those from a US population of comparable age, but neutrophil levels were notably lower in Guinea-Bissau. Conclusions The study indicated that eosinophil and platelet counts of infants were subject to seasonal variations. The reference ranges for haematological values were comparable to other African populations and corroborated that neutropenia regularly occurs in African infants.