Concurrent administration of inactivated hepatitis A vaccine with immune globulin in healthy adults.

301 healthy adult volunteers were randomized to one of three treatment groups: inactivated hepatitis A vaccine alone; inactivated hepatitis A vaccine with immune globulin (Ig) concurrently; or Ig alone. The first two treatment groups received a second dose of hepatitis A vaccine at week 24. Anti-HAV was measured 4, 8, 12, 24 and 28 weeks after the primary immunization. When comparing subjects receiving inactivated hepatitis A vaccine alone to those receiving vaccine and Ig, the seropositivity rates were not significantly different at 4, 8, 12 and 28 weeks, but at week 24 the seropositivity rate was lower in the group receiving both vaccine and Ig compared to the group receiving vaccine alone (92.0% compared to 97.0%). At weeks 8, 12 and 24 the geometric mean titers (GMTs) were significantly lower for subjects receiving both vaccine and Ig. The GMTs were not significantly different after the second dose of vaccine. At all time points, the lower serum antibody concentrations observed in subjects receiving both inactivated hepatitis A vaccine and Ig were nevertheless substantially higher than the cutoff for assay seropositivity and much higher than after Ig alone; these differences are therefore clinically insignificant.

Infecting dose and severity of typhoid: analysis of volunteer data and examination of the influence of the definition of illness used.

Data from volunteers challenged with Salmonella typhi were reanalysed to explore the relationship between challenge dose and severity of disease. Among 120 ill volunteers who received between 10(5) and 10(9) organisms, dose was weakly correlated with peak temperature (r = 0.22, 95% CI 0.04-0.39), duration of temperature above 103 degrees F (39.4 degrees C: r = 0.13, 95% CI - 0.03 to 0.55) and symptom score (r = 0.27, 95% CI 0.09-0.43). The association with symptom score was lost after adjusting for year, and the findings depended on the definition of illness used: with stricter definitions the associations with temperature were also lost. The study shows the need for caution in interpreting the relationship between dose and severity of disease.

Selective primary health care: strategies for control of disease in the developing world. XX. Typhoid fever.

The incidence of typhoid fever remains unacceptably high in developing countries. Because Salmonella typhi is disseminated by carriers, there is an urgent need to increase the rate of detection of carriers and to decrease the risk they pose to their communities. In urban areas where sewage disposal is lacking or inadequate, public water supplies are contaminated and typhoid fever is common. The contamination of food by carriers is the second commonest route of infection. Water purification processes lead to a rapid decline in the incidence of the disease; thus, many developing countries hope to develop pure water supplies for all citizens by the end of this century. Until this important public health goal is achieved, the use of vaccine, especially in children, could cause a significant decrease in the incidence of typhoid fever. A new oral attenuated vaccine promises to be effective and safe.

Anatomical and immunological responses of rabbit gallbladders to bacterial infections.

To study the sequential morphological and immunological response of the rabbit gallbladder to bacterial infection and to compare the inflammatory responses with different pathogens, gallbladders were infected with Streptococcus faecalis and two strains of Escherichia coli, one of which produced enterotoxin. Gallbladder infection was produced either by intravenously injecting bacteria into rabbits with a small liver infarct or by injecting bacteria directly into the gallbladder of normal rabbits. The percentage of gallbladders infected intravenously with a nonenterotoxigenic E. coli strain was 86% at 1 week, 70% at 3 weeks, and 15% at 6 weeks. Epithelial necrosis and leukocyte infiltration were prominent 1 week after infection. At 3 and 6 weeks after infection, there was crypt distortion and increased mucus secretion in the epithelium as shown by periodic acid-Schiff staining. The lamina propria was infiltrated with mononuclear cells, many of which were plasma cells. Myofibroblasts (contractile fibroblasts) were also identified on transmission microscopy, In addition to these changes, toxigenic E. coli produced subepithelial capillary dilation in the villus core. Morphological changes (excluding toxin-associated changes) were related to the duration of infection rather than to the specific species of infecting bacteria. Infected gallbladders studied by immunofluorescence had a greater than 50-fold increase in plasma cells compared with control cells. In addition, the number increased with the duration of infection. Immunoglobulin A cells were the major cell type in gallbladders infected by intravesical injection, whereas immunoglobulin G cells predominated in gallbladders infected intravenously. The gallbladder appears to mount a local immune response to bacterial infection.

Who introduced typhoid vaccination: Almroth Write or Richard Pfeiffer?

The British pathologist Almroth Wright generally is credited with the initiation of typhoid vaccination in 1896. His claims of priority were challenged as early as 1907 in favor of Richard Pfeiffer, a German bacteriologist and a student of Robert Koch. A review of the original literature of the 1890s and the early 1900s revealed that several groups were working on typhoid vaccine at the same time and that the credit for the initiation of typhoid vaccine studies should be shared by these two great researchers.

Biohydrogenation of cholesterol as an index of bacterial 7 alpha-dehydroxylase activity.

Fecal steroid compositions of 82 human subjects of various ages and diets and gastrointestinal status were examined by gas liquid chromatography. Progressive increases in bacterial activities on both bile acids and neutral sterols were observed with the advance of age in infants and children. The patterns in the 4-year-olds approached those observed in adults. Bacterial activities on fecal steroids were found to be decreased in adult subjects with acute shigellosis and in those challenged by castor oil. In contrast, no significant changes in fecal steroid profiles were observed in the subjects with traveller's diarrhea associated with toxigenic Escherichia coli. The effects of diarrhea on fecal steroids of infants under 1 1/2 years were less consistent than those of adults. However, a close relationship was observed between the degree of 7 alpha-dehydroxylation of cholic acid (expressed as the ratio of deoxycholic to the sum of deoxycholic and cholic acids) and the percentage of cholesterol in the feces (r = -0.921, p less than 0.001). The correlation between the production of lithocholic acid and the percentage cholesterol was also good (r = -0.739, p less than 0.001). Analysis of neutral steroids may be a good index of intraluminal bile acid metabolism.

Model of intraabdominal abscess in mice.

Intraperitoneal inoculation of sterile mouse feces into mice produced intraabdominal abscesses. The addition of Bacteroides fragilis increased the incidence and the number of abscesses.

Biohydrogenation of cholesterol as an index of bacterial 7α-dehydroxylase activity.

Fecal steroid compositions of 82 human subjects of various ages and diets and gastrointestinal status were examined by gas liquid chromatography. Progressive increases in bacterial activities on both bile acids and neutral sterols were observed with the advance of age in infants and children. The patterns in the 4-year-olds approached those observed in adults. Bacterial activites on fecal steroids were found to be decreased in adult subjects with acute shigellosis and in those challenged by castor oil. In contrast, no significant changes in fecal steroid profiles were observed in the subjects with traveller's diarrhea assoicated with toxigenicEscherichia coli. The effects of diarrhea on fecal steroids of infants under 1(1/2) years were less consistent than those of adults. However, a close relationship was observed between the degree of 7α-dehydroxylation of cholic acid (expressed as the ratio of deoxycholic to the sum of deoxycholic and cholic acids) and the percentage of cholesterol in the feces (r= 0.921, p<0.001). The correlation between the production of lithocholic acid and the percentage cholesterol was also good (r=-0.739, p<0.001). Analysis of neutral steroids may be a good index of intraluminal bile acid metabolism.

Genetic susceptibility to cholera.

In the course of studies of immunity to experimental cholera in man, 10(5) or 10(6) Vibrio cholerae were given to 66 college students and other community volunteers under quarantine in an isolation ward. HLA antigen and blood group determinations were carried out to test the hypothesis that severity of clinical cholera is dependent in part upon genetically-determined host susceptibility. Fifty-five volunteers developed diarrhoea; 38 had mild illness and 17 had severe cholera (stool volume greater than or equal to 5.0 litres). HLA antigens were found in similar frequency in volunteers with severe, mild or no diarrhoea; antigen A1, A2, A3 and B7 were most common. Blood group O, however, was found in 64% of persons with severe cholera versus 36-38% of volunteers with mild or absent illness. Thus, while no correlation was found between HLA type and severity of cholera, these results do support the claims of other investigators that blood group O is found more frequently in patients with severe cholera than in the normal population.

Immunity to enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli strains represent the most frequent etiological agent of travelers diarrhea. Challenge studies with several of these strains were undertaken in volunteers to evaluate the mechanisms of disease-induced immunity. Seventeen students and other community volunteers were given 10(6) or 10(8) organisms of E. coli B7A (O148:H28), which produces heat-labile and heat-stable enterotoxins. Ten individuals developed diarrheal illness closely resembling natural travelers diarrhea; of these ten, rises in titer of serum antitoxin and anti-O antibody occurred in eight (80%). Eight of the volunteers who developed diarrhea in the first test agreed to undergo rechallenge 9 weeks later with 10(8) B7A organisms. Only one of these eight "veterans" developed diarrhea versus seven of twelve controls given the same challenge (P = 0.05). Despite clinical protection, all "veterans" excreted B7A after rechallenge. Four controls who developed diarrhea during the homologous B7A rechallenge test were rechallenged 9 weeks later with 10(9) organisms of E. coli strain E2528-C1 (O25:H-), which produces only heat-labile enterotoxin and possesses a different O, H, and pili antigen composition than B7A. Three of four "veterans" and two of six controls developed comparable diarrhea. These studies demonstrate that prior disease due to enterotoxigenic E. coli confers homologous immunity against subsequent challenge, and the operative mechanism apparently is not bactericidal and is not mediated by serum anti-O antibodies. Heterologous protection was not conferred where the only common antigen was heat-labile enterotoxin, indicating that serum infection-derived antitoxin to heat-labile enterotoxin also is not protective.

The problem of emesis during oral glucose-electrolytes therapy given from the onset of severe cholera.

In an attempt to obviate the need for intravenous fluids by preventing dehydration, 57 adult volunteers who experienced induced clinical cholera during a vaccine development programme were treated from the onset of diarrhoea with oral glucose-electrolytes therapy. 44 individuals with mild to moderately profuse diarrhoea (less than 8 L. total volume) were maintained in normal water and electrolyte balance with oral therapy alone. 13 individuals with severe diarrhoea (greater than 8 L. total volume) could not be maintained in balance with oral therapy alone, due chiefly to emesis during the first day of illness. Emesis occurred in the absence of significant dehydration or acidosis. Since emesis precludes effective early oral therapy in severe cases, domiciliary oral therapy is unlikely to eliminate cholera mortality. Rural diarrhoea treatment centres using oral therapy with limited amounts of intravenous fluids when needed, could reduce case fatality from cholera and related diarrhoeas virtually to zero with least expense.

Immunity of cholera in man: relative role of antibacterial versus antitoxic immunity.

Purified cholera toxoid is antigenic when given enterally and orally. Purified toxoid fails to provide protection against experimental challenge. Clinical cholera confers formidable protection against homologous or heterologous rechallenge. Failure to culture vibrios from intestinal fluid or stool of re-challenge volunteers suggests that the predominant immune mechanism is antibacterial rather than antitoxic.