Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial

Objective To examine the protective efficacy of measles vaccination in infants in a low income country before 9 months of age

Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial

Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy)

Interleukin 7 from Maternal Milk Crosses the Intestinal Barrier and Modulates T- Cell Development in Offspring

Background Breastfeeding protects against illnesses and death in hazardous environments, an effect partly mediated by improved immune function. One hypothesis suggests that factors within milk supplement the inadequate immune response of the offspring, but this has not been able to account for a series of observations showing that factors within maternally derived milk may supplement the development of the immune system through a direct effect on the primary lymphoid organs. In a previous human study we reported evidence suggesting a link between IL-7 in breast milk and the thymic output of infants. Here we report evidence in mice of direct action of maternally-derived IL-7 on T cell development in the offspring. Methods and Findings  We have used recombinant IL-7 labelled with a fluorescent dye to trace the movement in live mice of IL-7 from the stomach across the gut and into the lymphoid tissues. To validate the functional ability of maternally derived IL- 7 we cross fostered IL-7 knock-out mice onto normal wild type mothers. Subsets of thymocytes and populations of peripheral T cells were significantly higher than those found in knock-out mice receiving milk from IL-7 knock-out mothers. Conclusions/Significance Our study provides direct evidence that interleukin 7, a factor which is critical in the development of T lymphocytes, when maternally derived can transfer across the intestine of the offspring, increase T cell production in the thymus and support the survival of T cells in the peripheral secondary lymphoid tissue

Beneficial non-targeted effects of BCG--ethical implications for the coming introduction of new TB vaccines

Non-targeted effect of BCG: Several recent studies suggest that BCG has beneficial non-targeted effects on general child survival in low-income countries. Studies of the effect of BCG on morbidity in humans are scarce; some found a positive effect of BCG and others show no effect. Non-targeted effects of vaccines-possible bias and confounding: The major argument against comparing vaccinated and unvaccinated groups is that there is a beneficial social selection bias for vaccinated children-the "Healthy vaccinee effect". However, controlling for various social and health-related background factors in the survival analyses had no effect on the estimates, making this source of bias less likely. A more powerful argument that the findings are not due to the healthy vaccinee effect is that differential non-targeted effects of other vaccines have been observed; diphteria-tetanus-pertussiss vaccination has marked negative effects on child survival, whereas measles vaccine has a positive effect in several studies. Several studies have shown better survival for children reacting to their BCG vaccination with a BCG scar or tuberculin skin test reaction (TST). It could be argued that the reacting children were immunologically stronger and therefore more likely to survive-the "Healthy reactor effect". However, recent findings show that a BCG scar and a TST reaction depend to a large extent on the vaccination technique. Hence, the BCG responses may reflect a true vaccine effect and not merely the health status of the children. Since HIV-1 has been shown to suppress both TST and BCG scar reaction in response to BCG, it is an obvious contributor to the healthy reactor effect, but excluding deaths of children with HIV-1 infection from analysis did not affect the beneficial effect of having a positive TST. Excluding children exposed to tuberculosis (TB) in the household did not affect the estimates either. Furthermore, there are strong sex-differential effects of BCG in both mortality and morbidity data, BCG being more beneficial for girls. These observations cannot consistently be explained by the healthy vaccinee or healthy reactor effects. Ethical implications: For future TB-vaccine studies, these findings imply that: These recommendations might be considered to delay or to be a too large obstacle for the development and trials of new TB vaccines. However, most of the non-targeted beneficial effects of BCG have been observed in children below 2 years of age, which is not a long follow-up time in a TB-vaccine trial. Furthermore, considering the difficulty in setting the TB diagnose in children and the lack of reliable TB-protection markers, it does not seem unreasonable to argue for monitoring of general morbidity and survival in future TB-vaccine trials

Bacillus Calmette-Guerin vaccination and infant mortality

When the bacillus Calmette-Guerin (BCG) vaccine was introduced in the 1920s, it was suggested that BCG occasionally had nonspecific beneficial effects on mortality beyond the specific protection against tuberculosis. Considering that BCG has since then become the most used vaccine in the world, surprisingly few studies have been undertaken into the effect of BCG on general mortality and morbidity. Recent studies suggest that BCG has beneficial nontargeted effects on general infant morbidity and mortality in low-income countries, often with the most pronounced effect among girls. These observational findings are supported by early trials in which children were randomized or alternated to BCG vaccination. Furthermore, a BCG scar and a positive tuberculin reaction are related to better survival among BCG-vaccinated children in low-income countries, especially for girls. The findings are not explained by frailty bias, in other words, that healthy children are more likely to receive BCG vaccination. A nonspecific, gender-differential effect of BCG on general infant mortality may have large implications for tuberculosis vaccine research and routine vaccination policy

Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial

Background and Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc. Patients/Methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC$_{0-inf,norm}$). Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC$_{0-inf,norm}$ was significantly greater for N9-GP than rFIXFc (ratio: 4.39; P < 0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound. Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc. Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25)

BCG scarring and improved child survival : a combined analysis of studies of BCG scarring

Bacillus Calmette–Guérin (BCG) vaccine against tuberculosis (TB) is recommended given at birth in TB-endemic areas. Currently, BCG vaccination programmes use “BCG vaccination coverage by 12 months of age” as the performance indicator. Previous studies suggest that BCG-vaccinated children, who develop a scar, have better overall survival compared with BCG-vaccinated children, who do not develop a scar. We summarized the available studies of BCG scarring and child survival. A structured literature search for studies with original data and analysis of BCG scarring and mortality. Combined analyses on effect of BCG scarring on overall mortality. We identified six studies covering seven cohorts, all from Guinea-Bissau, West Africa, with evaluation of BCG scarring amongst BCG-vaccinated children and follow-up for mortality. Determinants for BCG scarring were BCG strain, intradermal injection route, size of injection wheal, and co-administered vaccines and micronutrients. In a combined analysis, having a BCG scar vs. no BCG scar was associated with a mortality rate ratio (MRR) of 0.61 (95% CI: 0.51–0.74). The proportion with a BCG scar varied from 52 to 93%; the estimated effect of a BCG scar was not associated with the scar prevalence. The effect was strongest in the first (MRR = 0.48 (0.37–0.62)) and second (MRR = 0.63 (0.44–0.92)) year of life, and in children BCG-vaccinated in the neonatal period (MRR = 0.45 (0.36–0.55). The effect was not explained by protection against TB. Confounding and genetic factors are unlikely to explain the strong association between BCG scarring and subsequent survival. Including “BCG scar prevalence” as a BCG vaccination programme performance indicator should be considered. The effect of revaccinating scar-negative children should be studied