Neutropenia as an adverse event following vaccination : results from randomized clinical trials in healthy adults and systematic review

Background : In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance. Methodology : We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context. Principal Findings : Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations. Conclusions : It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events

The effects of resistant starch and whole grains on appetite, food intake and metabolic response.

With the rise in obesity, there has been an increased interest in foods which may beneficially affect appetite. Resistant starch (RS) and whole grains (of which RS is a main dietary fibre component) have been proposed to affect satiety and therefore may be beneficial in weight management. There is little direct evidence confirming this in humans. Whilst animal data suggest a positive effect of RS on appetite, the few existing human intervention studies provide inconsistent findings. For whole grains the majority of evidence is from epidemiological work as opposed to intervention studies. Therefore a series of studies was conducted to investigate effects of RS and whole grains on appetite and food intake. Two studies were conducted using RS. The first investigated the acute (24 hours) effects of 48 g RS in healthy adult males compared with an energy and available carbohydrate matched placebo. Following RS there was a significantly lower energy intake compared with placebo. There was also a significantly lower postprandial insulin response with RS, possibly explained by increased hepatic insulin clearance determined by a higher C-peptide to insulin ratio. In the second study 40 g RS consumed daily for 4 weeks was compared with the placebo, in overweight and obese participants. Effects on food intake were assessed and a frequently sampled intravenous glucose tolerance test (FSIVGTT) was conducted. This study found no effect on either appetite or energy intake, but did find significantly higher glucose, insulin and C-peptide concentrations, measured during the FSIVGTT, with the RS compared with the placebo, possibly explained by an improved first-phase insulin response. This finding did not translate into differences in parameters obtained from modelling the FSIVGTT data, but this and the lack of appetite and food intake differences could be explained by the small participant numbers. Two intervention studies were conducted with whole grains incorporated into bread rolls. The first, a crossover study, involved 3 weeks' daily consumption of 48 g milled whole grain or control, in young healthy adults. Whilst no significant difference was found between interventions in energy intake or subjective appetite ratings, a significantly lower systolic blood pressure was observed with the milled whole grains. The second was an 8 week parallel study (48 g intact or 48 g milled whole grains or control) in overweight and obese adults. No significant difference was found between groups on energy intake, subjective appetite ratings, cholesterol or postprandial metabolite concentrations. RS appears to be a possible satiating ingredient when consumed acutely and, whilst this was not confirmed in our chronic study, effects may have been masked by small participant numbers. A novel finding from our RS studies was an effect on the insulin response. These studies suggest that RS could have a beneficial role in weight management and favourable metabolic effects. Our whole grain interventions appear not to agree with epidemiological work that suggests a beneficial role on appetite, but there maybe effects on blood pressure regulation. In all instances further investigations are required in other population groups, with more participants and for longer time periods

The effects of resistant starch and whole grains on appetite, food intake and metabolic response.

With the rise in obesity, there has been an increased interest in foods which may beneficially affect appetite. Resistant starch (RS) and whole grains (of which RS is a main dietary fibre component) have been proposed to affect satiety and therefore may be beneficial in weight management. There is little direct evidence confirming this in humans. Whilst animal data suggest a positive effect of RS on appetite, the few existing human intervention studies provide inconsistent findings. For whole grains the majority of evidence is from epidemiological work as opposed to intervention studies. Therefore a series of studies was conducted to investigate effects of RS and whole grains on appetite and food intake. Two studies were conducted using RS. The first investigated the acute (24 hours) effects of 48 g RS in healthy adult males compared with an energy and available carbohydrate matched placebo. Following RS there was a significantly lower energy intake compared with placebo. There was also a significantly lower postprandial insulin response with RS, possibly explained by increased hepatic insulin clearance determined by a higher C-peptide to insulin ratio. In the second study 40 g RS consumed daily for 4 weeks was compared with the placebo, in overweight and obese participants. Effects on food intake were assessed and a frequently sampled intravenous glucose tolerance test (FSIVGTT) was conducted. This study found no effect on either appetite or energy intake, but did find significantly higher glucose, insulin and C-peptide concentrations, measured during the FSIVGTT, with the RS compared with the placebo, possibly explained by an improved first-phase insulin response. This finding did not translate into differences in parameters obtained from modelling the FSIVGTT data, but this and the lack of appetite and food intake differences could be explained by the small participant numbers. Two intervention studies were conducted with whole grains incorporated into bread rolls. The first, a crossover study, involved 3 weeks' daily consumption of 48 g milled whole grain or control, in young healthy adults. Whilst no significant difference was found between interventions in energy intake or subjective appetite ratings, a significantly lower systolic blood pressure was observed with the milled whole grains. The second was an 8 week parallel study (48 g intact or 48 g milled whole grains or control) in overweight and obese adults. No significant difference was found between groups on energy intake, subjective appetite ratings, cholesterol or postprandial metabolite concentrations. RS appears to be a possible satiating ingredient when consumed acutely and, whilst this was not confirmed in our chronic study, effects may have been masked by small participant numbers. A novel finding from our RS studies was an effect on the insulin response. These studies suggest that RS could have a beneficial role in weight management and favourable metabolic effects. Our whole grain interventions appear not to agree with epidemiological work that suggests a beneficial role on appetite, but there maybe effects on blood pressure regulation. In all instances further investigations are required in other population groups, with more participants and for longer time periods

Glucose concentrations from FSIVGTT after 4 weeks daily supplementation with 40 g HAM-RS2 or placebo.

<p>N = 12, mean ± SEM. No significant difference between the HAM-RS2 and placebo. Comparisons made with repeated measures ANOVA. Black circles  =  HAM-RS2; white circles  =  placebo; dashed line  =  baseline glucose concentrations.</p

Indices from the modelling of the data from the IVGTT.

<p>All values are mean (SEM), N = 12. Comparisons made with paired t-tests.</p

Insulin concentrations from FSIVGTT after 4 weeks daily supplementation with 40 g HAM-RS2 or placebo.

<p>N = 12, mean ± SEM. Significantly higher concentrations following HAM-RS2 compared with placebo (<i>p</i> = 0.009). Comparisons made with repeated measures ANOVA. Black circles  =  HAM-RS2; white circles  =  placebo.</p

C-peptide concentrations from FSIVGTT after 4 weeks daily supplementation with 40 g HAM-RS2 or placebo.

<p>N = 12, mean ± SEM. Significantly higher concentrations following HAM-RS2 compared with placebo (<i>p</i> = 0.016). Comparisons made with repeated measures ANOVA. Black circles  =  HAM-RS2; white circles  =  placebo.</p