[Vaccination in a developmental perspective].
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Adult↗
Biomedical subjects
Halvor Sommerfelt
Publications and source records attributed to Halvor Sommerfelt.
Community cohort study of Cryptosporidium parvum infections: sex-differential incidences associated with BCG and diphtheria-tetanus-pertussis vaccinations.
OBJECTIVE: Community studies in West Africa have suggested that routine vaccinations may have sex-differential non-targeted effects, the female-male mortality ratios being increased after receiving diphtheria-tetanus-pertussis (DTP) vaccination and reduced after administration of BCG or measles vaccine (MV). Using an existing data set, we examined whether vaccinations were associated with gender-differential incidences of Cryptosporidium parvum infection. METHODS: Two hundred children had been recruited shortly after birth and followed until 2 years of age or until follow-up was interrupted by a war. We performed weekly morbidity interviews and collected stool specimens, irrespective of whether the children had diarrhoea. Vaccination status for each child was classified according to the most recent vaccination with BCG, DTP, or MV. FINDINGS: The female-male incidence rate ratio (IRR) for Cryptosporidium infection among children who had received BCG as their last vaccine was 0.0 (95% CI: 0-3.49). However, among those who had received DTP as their last vaccine, the female-male IRR was 6.25 (2.06-18.9) for Cryptosporidium infection and 3.60 (0.91-14.2) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed significantly among BCG and DTP recipients (p=0.01). Among children who had received measles as their last routine vaccine, the female-male IRR was 1.57 (0.60-4.11) for Cryptosporidium infection and 0.98 (0.28-3.52) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed among DTP and MV recipients (p=0.02). For girls, early DTP vaccination compared with late or no DTP vaccination was associated with increased incidence rate of Cryptosporidium infection (IRR=4.23 (1.04-17.2)). For girls, the incidence rate decreased when they received MV. INTERPRETATION: Routine immunisations may affect morbidity for non-targeted infections. As in studies of infant mortality, BCG is associated with a low risk for girls relative to boys, whereas DTP is associated with a high female-male IRR of C. parvum infection.
Animals↗
[Protection against enterotoxigenic Escherichia coli infections].
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Cohort Studies↗
Identification and molecular characterization of the gene encoding coli surface antigen 20 of enterotoxigenic Escherichia coli.
Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea among children living in developing countries and of travelers' diarrhea. Current ETEC vaccine designs aim to induce an anti-colonizing immunity by including the ETEC surface colonization factor antigens. We isolated and characterized the structural gene of the coli surface antigen 20 (CS20). CS20 has an N-terminal amino acid sequence similar to that of CS18. We therefore used a DNA fragment carrying the CS18 fotA gene as a probe in a hybridization assay to detect the corresponding gene in a CS20-positive strain isolated from an Indian child. Cross hybridizing DNA was isolated and found to contain an open reading frame encoding a polypeptide of 195 amino acids, including a 22 amino acid signal peptide. The gene, which we named csnA, shows a high degree of identity to the major fimbrial subunits of CS12, CS18 and F6 (also referred to as 987P), a CS of porcine ETEC. The coding region of csnA was inserted into an expression system to generate a polypeptide confirmed to be CS20 by Western blot. A CS20 colony hybridization assay using a DNA probe derived from csnA was developed.
Antigens, Bacterial↗
Predictors of plasma zinc concentrations in children with acute diarrhea.
BACKGROUND: Plasma and serum zinc concentrations are the most widely used markers of zinc status in individual persons and populations. OBJECTIVE: The objective was to identify factors that influence plasma zinc concentrations during acute childhood diarrhea. DESIGN: This was a cross-sectional study of 1757 cases of acute diarrhea in 6-35-mo-old Nepalese children. The association between plasma zinc concentration and several clinical, anthropometric, socioeconomic, and biochemical variables was estimated in simple and multiple linear regression analyses. RESULTS: We observed a reduction in the mean plasma zinc concentration of 0.59 (95% CI: 0.44, 0.74) micro mol/L per degree ( degrees C) increase in axillary temperature. Having dysentery and an elevated plasma C-reactive protein concentration was also independently associated with lower plasma zinc. Children with clinical features of dehydration had higher plasma zinc concentrations than did those who were not dehydrated. Furthermore, a decrease in plasma albumin of 1 g/L was associated with a decrease in plasma zinc of 0.25 (95% CI: 0.21, 0.29) micro mol/L. The plasma albumin concentration confounded the associations between some clinical variables and plasma zinc, but the association between axillary temperature and dehydration on one hand and plasma zinc on the other was not substantially influenced by the albumin concentration. Moreover, the plasma zinc concentration increased with an increase in observed hemolysis. CONCLUSIONS: Dehydration, clinical and biochemical indicators of inflammation and hemolysis, and, when possible, plasma albumin concentrations should be taken into account when the plasma zinc concentration is used to estimate zinc status during episodes of diarrhea in childhood.
Acute Disease↗
Clonal relatedness of enterotoxigenic Escherichia coli strains isolated from a cohort of young children in Guinea-Bissau.
In a cohort study of 200 young children in Guinea-Bissau, it was previously found that some enterotoxigenic Escherichia coli (ETEC) strains were more pathogenic than others, depending on the type of toxin that they could produce, and that natural ETEC infections induced substantial protection against new infections with ETEC strains that had the same combination of toxins and colonization factors (CFs). We wanted to describe the clonal relatedness of the ETEC strains isolated during this study and to investigate whether the protective antigens and the virulence factors that were responsible for the pathogenic traits were common to strains that were clonally closely related or whether they were more likely to be encoded by the ETEC virulence plasmids that normally encode the toxins and the CFs. By performing repetitive sequence-based PCR analysis of strains representing 452 infections, we found that strains that had the same toxin-CF profile were usually closely related, although a few were unrelated. Strains that did not have the same toxin-CF profiles but that were positive for a given toxin or for a given CF were not consistently more closely related to each other than to strains that were negative for the same toxin or CF. Our results indicate that the pathogenic traits of ETEC were mainly attributed to genes carried on the ETEC virulence plasmids. Because most strains that had the same toxin-CF profile were closely related, it seems likely that the toxin-CF-specific protection was clonal and was not targeting antigens encoded by the virulence plasmids. These results are of relevance to the ETEC vaccine development effort.
Child↗
Cost-effectiveness of zinc as adjunct therapy for acute childhood diarrhoea in developing countries.
OBJECTIVE: To analyse the incremental costs, effects and cost-effectiveness of zinc used as adjunct therapy to standard treatment of acute childhood diarrhoea, including dysentery, and to reassess the cost-effectiveness of standard case management with oral rehydration salt (ORS). METHODS: A decision tree was used to model expected clinical outcomes and expected costs under four alternative treatment strategies. The best available epidemiological, clinical and economic evidence was used in the calculations, and the United Republic of Tanzania was the reference setting. Probabilistic cost-effectiveness analysis was performed using a Monte-Carlo simulation technique and the potential impacts of uncertainty in single parameters were explored in one-way sensitivity analyses. FINDINGS: ORS was found to be less cost-effective than previously thought. The use of zinc as adjunct therapy significantly improved the cost-effectiveness of standard management of diarrhoea for dysenteric as well as non-dysenteric illness. The results were particularly sensitive to mortality rates in non-dysenteric diarrhoea, but the alternative interventions can be defined as highly cost-effective even in pessimistic scenarios. CONCLUSION: There is sufficient evidence to recommend the inclusion of zinc into standard case management of both dysenteric and non-dysenteric acute diarrhoea.A direct transfer of our findings from the United Republic of Tanzania to other settings is not justified, but there are no indications of large geographical differences in the efficacy of zinc. It is therefore plausible that our findings are also applicable to other developing countries.
Acute Disease↗
Protection from natural infections with enterotoxigenic Escherichia coli: longitudinal study.
BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) are an important cause of diarrhoea and diarrhoeal deaths in children living in developing countries and of travellers' diarrhoea. During the past 25 years, vaccine development efforts have been focused on induction of protective immunity against surface colonisation factors (CFs) and the heat-labile enterotoxin. Although vaccines that induce immunity to heat-labile toxin offer protection against diarrhoea from ETEC that produce this toxin, the benefit of including CF antigens remains uncertain. We aimed to estimate the protection that natural ETEC infections induce against new infections. METHODS: In Guinea-Bissau, we followed up 200 neonates until up to age 2 years, most of whom were breastfed throughout the study. We collected stool specimens from the children every week irrespective of whether they had diarrhoea. As a measure of protection, we used Cox regression models to estimate the change in infection rates after a primary ETEC infection. We thus estimated the protection attributable to CFs, toxins, and to any other factors that could be shared by ETEC with the same toxin-CF profile. FINDINGS: ETEC infections induced a 47% (95% CI 12 to 69) protection against new infections with ETEC that had the same toxin-CF profile; the corresponding estimate attributable to CFs was -1% (-40 to 27). Infection with heat-labile toxin-positive ETEC conferred a 45% (-1 to 70) protection against symptomatic infections with ETEC positive for this toxin. INTERPRETATION: For breastfed children living in endemic areas, other antigens are substantially more important than CFs for induction of protective immunity against ETEC infection.
Diarrhea↗
Development and evaluation of genotypic assays for the detection and characterization of enterotoxigenic Escherichia coli.
We developed and evaluated a method to genotypically identify enterotoxigenic Escherichia coli (ETEC) and to characterize these organisms with respect to 18 of 21 known colonization factors (CFs). The method, which is based on polynucleotide DNA-DNA colony hybridization, includes a pooled toxin probe assay to identify ETEC, and individual probe assays to detect the enterotoxins STp, STh, and LT, and the CFs CFA/I, CS1-CS8, CS12-CS15, CS17-CS19, CS21, and CS22. We evaluated the pooled toxin probe assay during a cohort study of childhood diarrhea, and the individual probe assays against 33 reference strains and 92 clinical ETEC isolates. There was close to a complete agreement between the pooled toxin probe assay and the individual toxin probe assays, and between the individual CF probe assays and the corresponding phenotypic assays.
Antigens, Bacterial↗
Hypothesis: Vitamin A supplementation and childhood mortality: amplification of the non-specific effects of vaccines?
Most areas of health research will have accepted data and a dominating interpretation. If the interpretation is not correct, contradictions will accumulate, and it will eventually become clear that the current interpretation is untenable. In this situation, the best hypothesis is the one that accounts for all of the known data as well as the apparent contradictions. The area of vitamin A supplementation and childhood mortality in developing countries is afflicted with many contradictions and there is a need for a new hypothesis. We propose that the effect of vitamin A supplementation may depend on the amplification of non-specific effects of vaccines on childhood mortality.
Adjuvants, Immunologic↗
Effects of zinc deficiency and pneumococcal surface protein a immunization on zinc status and the risk of severe infection in mice.
Streptococcus pneumoniae is a major cause of illness and death in children in developing countries. In these children, zinc deficiency is associated with an increased risk of acute respiratory tract infections, which can be reduced by daily zinc administration. Severe infections decrease zinc levels in plasma and may thereby move individuals with preexisting low zinc stores into a vicious cycle of infection and unavailable zinc. Pneumococcal surface protein A (PspA) has emerged as a promising vaccine candidate, and immunization with this antigen protects animals from pneumococcal infection. In an animal experiment, we measured the effect of zinc depletion on the immune response to parenterally administrated PspA and assessed the effect of this PspA vaccination and zinc depletion on the severity of pneumococcal infection and on zinc status. Mice were kept on different diets for 5 weeks, immunized twice 14 days apart, and challenged intranasally with S. pneumoniae. Mice on the zinc-deficient diet showed substantially reduced immune responses to PspA, more extensive pneumococcal colonization in the nasal mucosa, more severe infections, and an increased risk of death. PspA immunization reduced the risk of severe disease, and the reduction in severity was reflected in substantially reduced zinc depletion from bones.
Animals↗
Intestinal and systemic immune responses to an oral cholera toxoid B subunit whole-cell vaccine administered during zinc supplementation.
Zinc plays a critical role in the normal functioning of the immune system. We investigated whether zinc sulfate administered orally to adult zinc-replete volunteers modulates systemic and intestinal immune responses to an oral killed cholera toxoid B subunit (CTB) whole-cell cholera vaccine. The 30 participants were immunized twice, with a 17-day interval. The vaccinees in the intervention group ingested 45 mg of elemental zinc thrice daily for 9 days starting 2 days before each vaccine dose. The median serum anti-CTB immunoglobulin A (IgA) and IgG responses from day 0 to day 30, i.e. after two vaccine doses, were 13-fold lower (P value for identical distribution, <0.005) in the zinc-supplemented compared to the nonsupplemented vaccinees. The median serum vibriocidal responses from baseline to after one (day 0 to day 17) and two (day 0 to day 30) vaccine doses were at least sixfold (P = 0.033) and fourfold (P = 0.091) higher, while the median fecal anti-CTB IgA response after two doses was estimated to be fourfold higher (P = 0.084) in the zinc-supplemented vaccinees. These observations show that zinc reduces the antitoxin and may enhance the antibacterial responses in serum. Zinc may also improve the intestinal antitoxin immune response. Oral zinc administration has the potential to modify critical immune responses to antigens applied to mucosal surfaces.
Administration, Oral↗
Cohort study of Guinean children: incidence, pathogenicity, conferred protection, and attributable risk for enteropathogens during the first 2 years of life.
We recruited 200 children shortly after birth and collected stool specimens weekly, irrespective of whether the children had diarrhea, until up to 2 years of age. All children were recruited during the first year of the study and were monitored for a median of 18.4 months. To measure pathogenicity, the odds ratio for diarrhea, adjusted for age, sex, and coinfections with other enteropathogens, was determined by logistic regression. Standard estimation of the population attributable risk indicated that rotavirus, enterotoxigenic Escherichia coli that produced only the heat-stable toxin ST, Isospora spp., Cryptosporidium parvum, Shiga toxin (Stx)-producing E. coli (STEC), and Shigella spp. or enteroinvasive E. coli were the most important contributors to diarrhea in this population. Stx2- but not Stx1-producing STEC strains were pathogenic. Enteroaggregative E. coli, diffusely adherent E. coli, and attaching-and-effacing E. coli strains, which were the most commonly isolated microorganisms, were not associated with diarrhea. For most of the microorganisms, primary infections did not confer protection against reinfection with the same organism, but some conferred protection against diarrhea from reinfection.
Age Factors↗
Enterotoxigenic Escherichia coli infections and diarrhea in a cohort of young children in Guinea-Bissau.
In an effort to describe the natural history of enterotoxigenic Escherichia coli (ETEC) infection and diarrhea, 200 children in Guinea-Bissau, West Africa, were followed up from birth until up to age 2 years with weekly stool specimen collection, regardless of whether the children had diarrhea. ETEC isolates were tested for the presence of the porcine and human heat-stable toxins (STp and STh), the heat-labile toxin (LT), and 18 of 21 known colonization factors (CFs). The rate of primary infections increased substantially after age 3 or 6 months (depending on the type of ETEC causing the infection). The pathogenicity of STh-containing ETEC was substantially higher than that of STp-containing ETEC, and STp and STh were associated with separate sets of CFs. Small epidemics were observed, mainly caused by STh-containing ETEC. The difference in epidemic propensity, CF association, and pathogenicity suggests that STh- and STp-containing ETEC represent 2 different groups of human ETEC. Vaccines should primarily target STh-containing ETEC.
Cohort Studies↗
Protective immunity after natural rotavirus infection: a community cohort study of newborn children in Guinea-Bissau, west Africa.
To study the natural history of rotavirus infection and to determine the protection it confers against reinfection and diarrhea, 200 newborns in Guinea-Bissau were prospectively followed for up to 2 years. Rotavirus was detected in stool specimens collected weekly. By age 2 years, the incidence of primary rotavirus infection was 74%. In the first 3 months of life, 17% of the infections were diarrhea associated, compared with 60% at 9-11 months; after age 18 months, all infections were asymptomatic. A primary infection conferred 52% (95% confidence interval [CI], 16% to 73%) and 70% (95% CI, 29% to 87%) protection against subsequent rotavirus infection and rotavirus diarrhea, respectively. The protection was 66% (95% CI, 24% to 85%) against reinfection within the same epidemic, compared with 34% (95% CI, -29% to 67%) against reinfection in any subsequent epidemic. The high level of protection against symptomatic rotavirus infection provides an important incentive for development of a rotavirus vaccine.
Cohort Studies↗
Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum.
OBJECTIVES: To evaluate the effect of daily zinc supplementation in children on the incidence of acute lower respiratory tract infections and pneumonia. DESIGN: Double masked, randomised placebo controlled trial. SETTING: A slum community in New Delhi, India. PARTICIPANTS: 2482 children aged 6 to 30 months. INTERVENTIONS: Daily elemental zinc, 10 mg to infants and 20 mg to older children or placebo for four months. Both groups received single massive dose of vitamin A (100 000 IU for infants and 200 000 IU for older children) at enrollment. MAIN OUTCOME MEASURES: All households were visited weekly. Any children with cough and lower chest indrawing or respiratory rate 5 breaths per minute less than the World Health Organization criteria for fast breathing were brought to study physicians. RESULTS: At four months the mean plasma zinc concentration was higher in the zinc group (19.8 (SD 10.1) v 9.3 (2.1) micromol/l, P<0.001). The proportion of children who had acute lower respiratory tract infection during follow up was no different in the two groups (absolute risk reduction -0.2%, 95% confidence interval -3.9% to 3.6%). Zinc supplementation resulted in a lower incidence of pneumonia than placebo (absolute risk reduction 2.5%, 95% confidence interval 0.4% to 4.6%). After correction for multiple episodes in the same child by generalised estimating equations analysis the odds ratio was 0.74, 95% confidence interval 0.56 to 0.99. CONCLUSIONS: Zinc supplementation substantially reduced the incidence of pneumonia in children who had received vitamin A.
Acute Disease↗
Clonal clustering and colonization factors among thermolabile and porcine thermostable enterotoxin-producing Escherichia coli.
A considerable proportion of enterotoxigenic Escherichia coli (ETEC) do not possess identifiable colonization factors (CFs). Genetic fingerprint analyses based on repetitive sequence-based polymerase chain reaction (rep-PCR) showed that 9 of 10 such CF-negative isolates which produced the thermolabile and the porcine thermostabile enterotoxin could be divided into three clusters. Following transformation with a plasmid harbouring the gene encoding CfaR, a positive regulator for several ETEC adhesins, three of the six strains in the first cluster expressed coli surface antigen 20 (CS20). No CFs were identified on the two transformed strains in the second cluster while the transformants of the two strains in the last cluster expressed CS12, the N-terminal amino acid sequence of which was deciphered. The study illustrates the potential of using genetic fingerprinting to group ETEC into clusters of strains with genes encoding different CFs and confirms the ability of CfaR to induce the expression of several different CFs.
Amino Acid Sequence↗
Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old children with acute diarrhea.
OBJECTIVE: To determine the efficacy of zinc-fortified oral rehydration salts solution (ORS) in comparison to ORS without zinc in 6- to 35-month-old urban children with acute diarrhea not sick enough to be hospitalized. DESIGN: Double-blind, randomized, controlled trial. METHODS: Children (n = 1219) with acute diarrhea were randomly assigned to one of 3 groups. The first group received a zinc syrup (15 mg zinc to 6- to 11-month-old children and 30 mg to 12- to 35-month-old children), the second group received zinc premixed with ORS (40 mg/L), and the control children received ORS only. Households were visited twice weekly until recovery. RESULTS: The total number of stools was lower in the zinc-ORS group (rate ratio, 0.83; 95% CI, 0.71-0.96), as was the proportion of children with watery stools (odds ratio, 0.61; 95% CI, 0.39-0.95), compared with the control group; there was no significant effect on diarrheal duration. ORS intake and proportion of children with vomiting were not significantly different between the zinc-ORS and control groups. The zinc syrup group had lower diarrheal duration (relative hazards, 0.89; 95% CI, 0.80-0.99) and total stools (rate ratio, 0.73; 95% CI, 0.70-0.77) than control children. CONCLUSIONS: Zinc-ORS was moderately efficacious in reducing the severity of acute diarrhea without increasing vomiting or reducing ORS intake.
Acute Disease↗