Safety and immunogenicity of AS03B adjuvanted split virion versus non-adjuvanted whole virion H1N1 influenza vaccine in UK children aged 6 months-12 years: open label, randomised, parallel group, multicentre study.

OBJECTIVES: To compare the safety, reactogenicity, and immunogenicity of an adjuvanted split virion H1N1 vaccine and a non-adjuvanted whole virion vaccine used in the pandemic immunisation programme in the United Kingdom. DESIGN: Open label, randomised, parallel group, phase II study. SETTING: Five UK centres (Oxford, Southampton, Bristol, Exeter, and London). PARTICIPANTS: Children aged 6 months to less than 13 years for whom a parent or guardian had provided written informed consent and who were able to comply with study procedures were eligible. Those with laboratory confirmed pandemic H1N1 influenza or clinically diagnosed disease meriting antiviral treatment, allergy to egg or any other vaccine components, or coagulation defects, or who were severely immunocompromised or had recently received blood products were excluded. Children were grouped by age: 6 months-<3 years (younger group) and 3-<13 years (older group). Recruitment was by media advertising and direct mailing. Recruitment visits were attended by 949 participants, of whom 943 were enrolled and 937 included in the per protocol analysis. INTERVENTIONS: Participants were randomised 1:1 to receive AS03(B) (tocopherol based oil in water emulsion) adjuvanted split virion vaccine derived from egg culture or non-adjuvanted whole virion vaccine derived from cell culture. Both were given as two doses 21 days apart. Reactogenicity data were collected for one week after immunisation by diary card. Serum samples were collected at baseline and after the second dose. MAIN OUTCOME MEASURES: Primary reactogenicity end points were frequency and severity of fever, tenderness, swelling, and erythema after vaccination. Immunogenicity was measured by microneutralisation and haemagglutination inhibition assays. The primary immunogenicity objective was a comparison between vaccines of the percentage of participants showing seroconversion by the microneutralisation assay (fourfold rise to a titre of >or=1:40 from before vaccination to three weeks after the second dose). RESULTS: Seroconversion rates were higher after the adjuvanted split virion vaccine than after the whole virion vaccine, most notably in the youngest children (163 of 166 participants with paired serum samples (98.2%, 95% confidence interval 94.8% to 99.6%) v 157 of 196 (80.1%, 73.8% to 85.5%), P<0.001) in children under 3 years and 226 of 228 (99.1%, 96.9% to 99.9%) v 95.9%, 92.4% to 98.1%, P=0.03) in those over 3 years). The adjuvanted split virion vaccine was more reactogenic than the whole virion vaccine, with more frequent systemic reactions and severe local reactions in children aged over 5 years after dose one (13 (7.2%, 3.9% to 12%) v 2 (1.1%, 0.1% to 3.9%), P<0.001) and dose two (15 (8.5%, 4.8% to 13.7%) v 2 (1.1%, 0.1% to 4.1%), P<0.002) and after dose two in those under 5 years (15 (5.9%, 3.3% to 9.6%) v 0 (0.0%, 0% to 1.4%), P<0.001). Dose two of the adjuvanted split virion vaccine was more reactogenic than dose one, especially for fever >or=38 masculineC in those aged under 5 (24 (8.9%, 5.8% to 12.9%) v 57 (22.4%, 17.5% to 28.1%), P<0.001). CONCLUSIONS: In this first direct comparison of an AS03(B) adjuvanted split virion versus whole virion non-adjuvanted H1N1 vaccine, the adjuvanted vaccine, while more reactogenic, was more immunogenic and, importantly, achieved high seroconversion rates in children aged less than 3 years. This indicates the potential for improved immunogenicity of influenza vaccines in this age group. TRIAL REGISTRATION: Clinical trials.gov NCT00980850; ISRCTN89141709.

Early-life nutritional and environmental determinants of thymic size in infants born in rural Bangladesh.

AIM: The aim was to assess the impact of nutritional status and environmental exposures on infant thymic development in the rural Matlab region of Bangladesh. METHODS: In a cohort of N(max) 2094 infants born during a randomized study of combined interventions to improve maternal and infant health, thymic volume (thymic index, TI) was assessed by ultrasonography at birth and at 8, 24 and 52 weeks of age. Data on birth weight, infant anthropometry and feeding status were also collected. RESULTS: At all ages, TI was positively associated with infant weight and strongly associated with the month of measurement. Longer duration of exclusive breastfeeding resulted in a larger TI at 52 weeks. TI at birth and at 8 weeks correlated positively with birth weight, but by 24 and 52 weeks and when adjusted for infant weight this effect was no longer present. Thymic size was not affected by pre-natal maternal supplementation or by socioeconomic status but was correlated to arsenic exposure during pregnancy. CONCLUSION: In this population of rural Bangladeshi infants, thymic development is influenced by both nutritional and environmental exposures early in life. The long-term functional implications of these findings warrant further investigation.

Birth season and environmental influences on patterns of thymic growth in rural Gambian infants.

AIM: In rural Gambia, birth season predicts infection-related adult mortality. Seasonal factors in early life may programme the immune system, possibly via an effect on thymic development. This study tested whether thymus size in rural Gambian infants is affected by birth season, defined as January-June (harvest, few infections) versus July-December (hungry, high infectious load). METHODS: Thymic volume (thymic index) was assessed sonographically at 1, 8, 24 and 52 wk in 138 singleton infants born over 14 consecutive months. Growth and morbidity were regularly assessed. RESULTS: Mean thymic index increased from 19.9 at 1 wk to 30.9 at 8 wk and 35.7 at 24 wk, then fell to 32.0 at 52 wk. Thymic index was associated with each preceding thymic index up to 24 wk. This tracking persisted after correcting for infant weight and month of measurement (p < 0.01). Thymic index at 1 wk was marginally but non-significantly lower in hungry season births (p = 0.06). Thymic index was lower in hungry season measurements; this effect persisted after adjusting for current weight and infection markers, and was strongest at 8 wk (p = 0.001). CONCLUSION: These results describe a pattern of thymic growth followed by diminution in size. An infant's thymic index tracks despite changes in body weight and season. Thymic index was lower in the hungry season. This appears not to be explained by infection or nutritional status. A possible influence of trophic factors in breast milk merits investigation.

Seasonal programming of adult longevity in Ukraine.

Longevity was significantly associated with season of birth in 101,634 individuals who died in Kiev during the period 1990-2000. The relationship between age at death and month of birth showed a very similar pattern for both men and women. Mean values for the age at death were lowest for subjects born in April-July, and highest for individuals born at the beginning and end of the year. Minimum and maximum ages at death, analysed according to month of birth, differed by 2.6 years in men and 2.3 years in women. For all major causes of death causes, the mean age at death for persons born in the fourth quarter was the highest. These results suggest that, in this population, longevity is affected by prenatal or early postnatal seasonal factors. This is consistent with the hypothesis that the rate of ageing may be programmed in response to environmental influences at critical periods of early development.

Leptin, malnutrition, and immune response in rural Gambian children.

BACKGROUND: The adipocyte derived hormone, leptin, has cytokine like function and may mediate the effects of starvation on immunity. Mice with congenital leptin deficiency (ob/ob) have small hypocellular thymuses and impaired cellular immunity. In humans leptin influences the differentiation of naïve and memory cells in vitro, and genetic leptin deficiency has been associated with an ill defined susceptibility to infection. AIMS: To describe the in vivo relation of leptin and immune function in children. METHODS: Fasting plasma leptin concentrations, immune function (T and B cell mediated vaccine responses and delayed type hypersensitivity), and mucosal function (dual sugar permeability test and salivary sIgA concentrations) were measured in a cohort of 472 moderately undernourished rural Gambian children. RESULTS: Leptin concentrations correlated with body fat assessed by mid upper arm circumference or BMI for age Z scores, and were very low compared to well nourished European norms (males 1.8 v 11.1 ng/ml; females 2.4 v 13.8 ng/ml). No detectable relations were found between leptin concentrations and any of the measures of immune or mucosal function. CONCLUSIONS: The data confirm that leptin acts as a peripheral signal of energy restriction, but do not support an association between fasting plasma leptin levels and immune function in children of this age.

Immune function in rural Gambian children is not related to season of birth, birth size, or maternal supplementation status.

BACKGROUND: We previously showed that mortality from infectious diseases among young adults in rural Gambia is strongly correlated with the season of their birth. This suggests that early life insults that involve fetal malnutrition, exposure to natural toxins, or highly seasonal infections affecting the infant or pregnant mother cause permanent damage to the immune system. Excess mortality begins after puberty and has a maximal odds ratio of >10 for deaths between ages 25 and 50 y. OBJECTIVE: We investigated the immune function of children according to birth weight, season of birth, and exposure to maternal dietary supplementation during pregnancy. DESIGN: Immune function was measured in 472 prepubertal children aged 6.5-9.5 y from 28 villages in rural Gambia. The mothers of these children had been randomly assigned to a high-energy prenatal supplementation program, which significantly increased birth weight. This permitted supplementation status, birth weight, and season of birth to be investigated as exposure variables. The outcome variables tested were naive responses to rabies and pneumococcus vaccines, delayed-type hypersensitivity skin reactions, and mucosal defense (secretory immunoglobulin A and dual-sugar permeability). RESULTS: Immune responses were strongly related to current age and sex, suggesting a high level of sensitivity, but were not consistently related to birth weight, season of birth, or maternal supplementation (control compared with intervention). CONCLUSION: Events in early life did not predict a measurable defect in immune response within this cohort of rural Gambian children. It is possible that the early programming of immune function may be mediated through a defect in immunologic memory or early senescence rather than through impairment of early responses.

Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa.

BACKGROUND: Research over the past decade has suggested that prenatal and early postnatal nutrition influence the risk of developing chronic degenerative diseases up to 60 years later. We now present evidence that risk of death from infectious diseases in young adulthood is similarly programmed by early life events. METHODS: In three rural Gambian villages, affected by a marked annual seasonality in diet and disease, we have kept detailed demographic, anthropometric and health records since 1949. Fate was known with certainty for 3,162 individuals (2,059 alive/1,103 dead, most dying in childhood). For this case-control analysis of antecedent predictors of premature mortality, all adult deaths (n = 61) were paired with two randomly selected controls matched for sex and year of birth. RESULTS: Mean age at death was 25 (SD: 8) years. Adult death was associated with a profound bias in month of birth with 49 cases born in the nutritionally-debilitating hungry season (Jul-Dec) versus 12 in the harvest season (Jan-Jun). Relative to harvest season the hazard ratio for early death in hungry-season births rose from 3.7 (for deaths >14.5 years, P = 0.000013) to 10.3 (for deaths >25 years, P = 0.00002). Anthropometric and haematological status at 18 months of age was identical in cases and controls, indicating an earlier origin to the defect. Most deaths for which cause was known had a definite or possible infectious aetiology; none were from degenerative diseases of affluence. CONCLUSIONS: Early life exposures, correlated with season of birth, strongly influence susceptibility to fatal infections in young adulthood. The evidence suggests that nutritionally-mediated intrauterine growth retardation may permanently impair the development of immune function.

PIP: This paper presents the influence of prenatal and early postnatal nutrition on the risk of developing chronic degenerative diseases during late adulthood. Investigation of the thrifty phenotype hypothesis using 1949 birth records in three rural Gambian villages illustrates the severity of seasonality in diet and disease patterns. A database of 3162 individuals--2059 survivors and 1103 fatalities--was examined. Using a case-control analysis of antecedent predictors of premature mortality, all deaths were paired with two randomly selected controls matched for sex and year. Results revealed that the mean age at death was 25 years, with 49 adult death cases occurring in the nutritionally debilitating hungry season compared to 12 cases occurring during the harvest season. In relation to the harvest season, the hazard ratio rose from 3.7 (for deaths at age 14.5 years; p = 0.000013) to 10.3 (for deaths at age 25 years; p = 0.00002). Both the anthropometric and hematological status at 18 months was similar in cases and controls, with most deaths caused by a definite or possible infectious etiology without evidence of degenerative disease cause. This study concludes that early life exposures correlated with season of birth significantly influence the susceptibility to fatal infections in young adulthood. This also suggests that nutritionally mediated intrauterine growth retardation could permanently impair the development of immune function.