Mass vaccination of children with pertussis toxoid--decreased incidence in both vaccinated and nonvaccinated persons.

During 1979-1995, there was no vaccination against pertussis in Sweden. With the aim of studying the epidemiology and transmission of pertussis, mass vaccination with pertussis toxoid of children born during the 1990s was instituted in the Göteborg area (population, 778,597) in 1995. Infants were offered 3 doses of pertussis toxoid combined with diphtheria and tetanus toxoids. Children aged > or =1 year were offered 3 doses of pertussis toxoid alone. From June 1995 through February 1999, 167,810 doses of pertussis toxoid were given to 61,219 children born during the 1990s (56% received 3 doses). The number of Bordetella pertussis isolates per year declined from 1214 (1993-1995) to 64 (January 1997 through June 1999; P<.0001), and hospitalizations due to pertussis declined from 62 to 5 (P<.0001). Significant decreases in B. pertussis isolates and hospitalizations occurred in all age groups, including adults and nonvaccinated infants. Thus, mass vaccination of children with pertussis toxoid decreases spread of B. pertussis in the population.

Serotypes and clinical manifestations of group B streptococcal infections in western Sweden.

OBJECTIVES: To study the serotype distributions of group B streptococci (GBS) isolated from blood and cerebrospinal fluid and from the genital tract of pregnant women and to investigate any possible relation between serotype, age and clinical manifestation. METHODS: Invasive strains were collected from 1988 to 1997 and genital strains from 1995 to 1996. Strains of GBS were serotyped with coagglutination. Clinical data were obtained from hospital notes. RESULTS: A total of 144 invasive strains, 78 from neonates and infants and 66 from adults, were serotyped. The most common isolates from neonates and infants were types III (62%), Ia (18%), and V (9%). The most common isolates from adults were types III (29%), Ib (23%), V (21%) and II (15%). A majority of the adults (94%) had an underlying medical condition. The most common serotypes of the 114 strains isolated from the genital tract of pregnant women were types III (32%), V (22%), Ia (13%), Ib (13%) and II (11%). CONCLUSIONS: Serotype III was the single most frequent GBS isolate from infants and adults. Serotype V, which appeared first in 1992, was the third most frequent isolate. A vaccine containing five GBS capsular polysaccharides appears to be appropriate for the Swedish population.

Parapertussis and pertussis: differences and similarities in incidence, clinical course, and antibody responses.

OBJECTIVES: To compare the incidence, clinical course, and serologic response to Bordetella antigens in patients with parapertussis and pertussis. DESIGN: Two studies were performed in Sweden during the 1990s, when pertussis vaccines were used only in clinical trials. Study I was a retrospective study of patients with positive Bordetella cultures obtained in clinical routine, and study II involved an active search for patients with Bordetella infections during a placebo-controlled trial of a pertussis toxoid vaccine. RESULTS: Study I includes 58, and study II 23 patients with parapertussis. In study I, the incidence of parapertussis was 0.016 cases per 100 person years in children 0 to 6 years old and 0 in older children and adults. In study II, the incidence rates of parapertussis and pertussis were 0.2 and 16.2 per 100 person years, respectively, in children followed from 3 months to 3 years of age. The median number of days with cough was 21 in parapertussis and 59 in pertussis. The proportions of children with whooping and vomiting were lower in parapertussis than in pertussis. Geometric mean serum filamentous hemagglutinin IgG increased from 6 to 63, and pertactin IgG from 4 to 12 units/mL in parapertussis patients, which was similar to increases in children with pertussis. CONCLUSIONS: Disease caused by Bordetella parapertussis is diagnosed less commonly and is milder and of shorter duration than disease caused by Bordetella pertussis. Parapertussis induced serum IgG against filamentous hemagglutinin and pertactin of similar magnitude as does pertussis, and did not induce serum IgG against pertussis toxin.

Evaluation of PCR for diagnosis of Bordetella pertussis and Bordetella parapertussis infections.

PCR, using primers Plp1 and Plp2, was evaluated for the detection of DNA from Bordetella pertussis in bacterial strains and in nasopharyngeal samples from patients with a cough lasting at least 7 days. The assay could detect DNA from 6 CFU of B. pertussis/10 microl of sample. Results of the PCR assay were compared with those of cultures, a determination of serum antibodies against pertussis toxin and filamentous hemagglutinin, and a clinical evaluation of 2,442 coughing episodes. The overall sensitivity of PCR was 65% (623 of 956), which was higher than the sensitivity of cultures (58%) (P < 0.001). Factors influencing the sensitivity of PCR were the interval between the onset of symptoms and sampling and the vaccination status of the patient. The specificity of PCR was 98% (1,451 of 1,486). The positive and negative predictive values were 95 and 81%, respectively. Parapertussis PCR, using primers BPPA and BPPZ, was positive in 11 of 18 culture-positive cases and was confirmed by serology in another 4 cases. In conclusion, PCR is a valuable complement to cultures and can probably replace cultures for diagnosis of B. pertussis and Bordetella parapertussis infections.

Determination of moisture in hard gelatin capsules using near-infrared spectroscopy: applications to at-line process control of pharmaceutics.

A method is proposed in which diffuse reflectance near-infrared spectroscopy (NIR) is applied in an at-line process analytical interface to determine moisture content in bulk hard gelatin capsules. Capsule samples were equilibrated at various relative humidities and the moisture contents were determined using loss on drying (LOD). Different multivariate calibration methods using multiple linear regression (MLR) and partial least squares regression (PLSR) and various spectral pretreatments were compared. No sample pretreatment was required and the analysis time was 1-2 min. The investigated range for the moisture determination was 5.6-18.0% w/w and the root mean square error of prediction (RMSEP) value was 0.1% w/w.

Efficacy of a monocomponent pertussis toxoid vaccine after household exposure to pertussis.

In a double-blind, placebo-controlled efficacy trial of a monocomponent pertussis toxoid vaccine, 3450 infants were randomly assigned to vaccination with diphtheria-tetanus toxoids with or without pertussis toxoid at 3, 5, and 12 months of age. Study children and family members were investigated for possible pertussis with cultures, serology, and polymerase chain reaction. Efficacy was 71% after 3 dose when the World Health Organization case definition of pertussis (which includes paroxysmal cough for 21 days or longer) was used. We report the efficacy in the subgroup of children who were exposed to pertussis in the household. Among study children exposed to pertussis in the household from the day of the third vaccination, 20 of 99 (20%) recipients of diphtheria-tetanus-pertussis toxoids vaccine and 64 of 79 (81%) recipients of diphtheria-tetanus toxoids vaccine had pertussis fulfilling criteria of the World Health Organization. The vaccine efficacy was 75% (95% confidence intervals 64% to 84%). In children who had received only two doses at the time of household exposure, vaccine efficacy was 66% (95% confidence intervals 15% to 90%) based on 4 cases among 32 household-exposed recipients of diphtheria-tetanus-pertussis toxoids vaccine and 13 cases among 35 household-exposed recipients of diphtheria-tetanus toxoids vaccine. In conclusion, the pertussis toxoid vaccine provides protection against pertussis both after household and community exposure.

Unchanged efficacy of a pertussis toxoid vaccine throughout the two years after the third vaccination of infants.

BACKGROUND: In a previously reported double blind efficacy trial of a pertussis toxoid vaccine, 3450 infants were randomized to receive diphtheria-tetanus toxoids with or without pertussis toxoid at 3, 5 and 12 months of age. Efficacy against pertussis as defined by the World Health Organization was 71% from 30 days after the third vaccination with an average follow-up of 17.5 months. We now report efficacy for an additional 6 months of open follow-up. METHODS: Parents were contacted monthly by a nurse. If a participant or a family member coughed for > or = 7 days, a nasopharyngeal sample and paired sera were obtained. RESULTS: Efficacy during this open follow-up period was 77% (95% confidence intervals, 66 to 85%) based on 29 and 110 cases fulfilling the WHO definition of pertussis in vaccinated and control children, respectively. Efficacy against household exposure was 76% (95% confidence intervals, 51 to 91%). Pertussis in vaccinated children had a significantly shorter duration than pertussis in control children. Determination of pertussis toxin antibodies in paired sera with enzyme-linked immunosorbent assay had a lower diagnostic sensitivity in vaccinated (45%) than in control (92%) children, while determination of antibodies against filamentous hemagglutinin (not included in the vaccine) was highly sensitive for diagnosing pertussis in both groups (100 and 90%, respectively). CONCLUSIONS: A monocomponent pertussis toxoid vaccine induces significant protection against pertussis for at least 2 years after the third injection. To obtain an unbiased estimate of vaccine efficacy it is important to determine antibodies against an antigen that is not included in the vaccine.

A placebo-controlled trial of a pertussis-toxoid vaccine.

BACKGROUND: Although many whole-cell vaccines have been effective in preventing pertussis, these vaccines are difficult to standardize and can produce side effects. In Sweden, pertussis became endemic during the 1970s despite vaccination. Because of its limited efficacy, the Swedish-made whole-cell vaccine was withdrawn in 1979. METHODS: To evaluate the efficacy of an acellular vaccine consisting of pertussis toxin inactivated by hydrogen peroxide (pertussis toxoid), we conducted a randomized, double-blind, placebo-controlled trial in Sweden. Infants were vaccinated with either diphtheria and tetanus toxoids alone (DT toxoids, 1726 infants) or diphtheria, tetanus, and pertussis toxoids (DTP toxoids, 1724 infants) at 3, 5, and 12 months of age. RESULTS: There were no serious reactions. With the pertussis vaccine there were slightly more local reactions than with the DT toxoids alone, but the rates of postvaccination fever were the same. The main period of surveillance, which began 30 days after the third vaccination, continued for a median of 17.5 months. There were 312 cases of pertussis (72 in the DTP-toxoids group and 240 in the DT-toxoids group) that met the clinical criterion (paroxysmal cough lasting > or = 21 days) and laboratory criteria for pertussis as defined by the World Health Organization. The efficacy of this acellular vaccine was 71 percent (95 percent confidence interval, 63 to 78 percent). The recipients of DTP toxoids who had pertussis had cough of shorter duration than the recipients of DT toxoids, and fewer had whooping and vomiting. The vaccine efficacy after two doses was 55 percent (95 percent confidence interval, 12 to 78 percent), on the basis of 14 cases in the DTP-toxoids group and 31 in the DT-toxoids group that met the definition of the World Health Organization. CONCLUSIONS: A pharmacologically inert, acellular pertussis-toxoid vaccine that is easily standardized is safe and confers substantial protection against pertussis.

Accelerated dissolution rate analysis (ACDRA) for controlled release drugs. Application to Roxiam.

Accelerated dissolution rate analysis by elevated temperature has been applied to the release of remoxipride from a controlled release drug. Roxiam, and compared to the standard USP method. A PLS model has been used in evaluating the factors of importance of the release as well as for the comparison to the standard USP method. Accelerated Dissolution Rate Analysis (ACDRA) offers the possibility of substantial reduction of analysis time. The time needed for one analysis with ACDRA is less than 5% of the USP-method. The automated analytical procedure is well suited for use in process control as well as in the early stages of the formulation development.

Response and decline of serum IgG antibodies to pertussis toxin, filamentous hemagglutinin and pertactin in children with pertussis.

The serum IgG antibody response and decrease to 3 Bordetella pertussis antigens was compared in children with pertussis. Sera were obtained at the first clinical visit and 1, 3 and 12 months later from 89 children with > or = 3 weeks of paroxysmal cough. IgG antibodies to pertussis toxin (PT), to filamentous hemagglutinin (FHA) and to pertactin were determined with ELISA. Of 54 children with culture-confirmed pertussis or culture-confirmed familial exposure, 45 (83%) had a significant (> or = 3 fold) increase in PT IgG and 40 (74%) in FHA IgG antibodies, while only 29 (54%) had a significant increase in pertactin IgG antibodies. Significant decreases in PT, FHA and pertactin IgG antibodies were found in 34 (63%), 9 (17%) and 28 (52%) children, respectively. In the remaining 35 who did not have culture-confirmed disease, significant PT and/or FHA IgG antibody increases (criteria for pertussis according to the WHO definition) were found in 17 (49%). Only 6 of these 17 children had a significant pertactin IgG antibody increase. Of the remaining 18 children (who did not fulfil WHO criteria for pertussis), significant decreases in PT and/or FHA IgG antibodies were found in 13. We conclude that a serum IgG reaction to PT and FHA occurs in almost all children with pertussis. An increase in pertactin IgG antibodies occurs less frequently than against PT and FHA. Significant decreases in PT or FHA IgG antibodies in children with clinical pertussis might be of use as a diagnostic criterion in children brought late for examination.

How common is whooping cough in a nonvaccinating country?

In Sweden general vaccination with a whole cell pertussis vaccine was recommended from 1953. In 1979 the recommendation was withdrawn because the Swedish-made vaccine had become ineffective. In order to determine the incidence of the disease in a nonvaccinating country, 400 children born in 1980 were randomly selected from the population register of Göteborg, Sweden. The parents of the children were interviewed in 1990, when the children were 10 years old. The parents of 377 children could be reached, and of those 372 were not vaccinated against pertussis. Of the nonvaccinated children 61% had experienced clinically typical whooping cough; 195 (119 with and 76 without a history of whooping cough) agreed to donate a serum sample for determination of antibodies against pertussis toxin, filamentous hemagglutinin and pertactin. Of the children with a history of whooping cough, 91% had antibodies against pertussis toxin, as had 64% of the children without a history of disease. All but 3 children had antibodies against filamentous hemagglutinin and all 195 children had antibodies against pertactin. The antibody titers against the 2 last mentioned proteins did not differ between children with and without a history of whooping cough or between children with and without antibodies against pertussis toxin.

Serum antibodies against a 69-kilodalton outer-membrane protein, pertactin, from Bordetella pertussis in nonvaccinated children with and without a history of clinical pertussis.

Serum antibodies against pertactin were found in all samples from 260 nonvaccinated healthy Swedish 1- to 4-year-old children, although 42% had neither a history of clinical pertussis nor antibodies against pertussis toxin or filamentous hemagglutinin. Pertactin antibody levels were, however, higher in children with a history of pertussis than in those without a history of pertussis, and higher in children with antibodies against pertussis toxin and filamentous hemagglutinin than in those without such antibodies.

Immunoglobulin A antibodies to pertussis toxin and filamentous hemagglutinin in saliva from patients with pertussis.

Immunoglobulin A (IgA) antibodies against pertussis toxin (PT) and filamentous hemagglutinin (FHA) in 181 saliva samples obtained during various stages of pertussis from 112 patients were determined. Saliva samples obtained within 5 days after the onset of symptoms did not have detectable IgA antibodies against either of the two antigens. Of the samples obtained between 6 and 50 days after the onset of symptoms, 72% had antibodies against FHA but only 40% had antibodies against PT. With few exceptions, saliva samples obtained more than 50 days after the onset of symptoms contained antibodies against both antigens. In the 59 patients from whom paired saliva samples were obtained at intervals of 2 to 5 weeks, a significant increase in the geometric mean FHA antibody titers but not PT antibody titers occurred. However, increases that were fourfold or greater were observed against FHA in only 19 patients and against PT in 14 patients. Thus, IgA antibodies against FHA and PT in saliva develop during pertussis, and the importance of secretory IgA antibodies for protection against infection and disease should be investigated. Determination of these antibodies in paired saliva samples is, however, of little value for the laboratory diagnosis of pertussis.

Immunogenicity and safety of a pertussis vaccine composed of pertussis toxin inactivated by hydrogen peroxide, in 18- to 23-month-old children.

A new pertussis vaccine, composed of purified pertussis toxin inactivated by hydrogen peroxide and adsorbed onto aluminum hydroxide (NICHD-Ptxd), was injected into 60 children aged 18 to 23 months without a history of pertussis or pertussis vaccination. Two doses of toxoid, 10 and 50 micrograms, were used. Two injections, given 8 to 12 weeks apart, elicited increases in serum levels of antitoxin and IgG antibodies in 56 children who had no detectable antitoxin (less than 5 units) before vaccination. Four children with detectable antitoxin (greater than or equal to 5 units) before the first vaccination had pronounced antibody increases after the first dose. After the second dose, the geometric mean antitoxin concentration was 29 units with the 50 micrograms dosage and 10 units with the 10 micrograms dosage (p less than 0.001). Serum antibody levels elicited by two injections of 50 micrograms were similar to those in patients convalescing from pertussis. A third injection given to seven children 9 to 10 months after the second injection gave a booster response, with high levels of antitoxin (160 to 1280 units) and of IgG antibodies. With few exceptions the antibody response was restricted to the IgG class. Transient local reactions greater than or equal to 2 cm in diameter occurred in 14% of the children after the first dose and in 44% after the second and third doses. Moderate fever was recorded after 6% of all injections. There were no changes in peripheral blood leukocyte counts or fasting blood glucose levels measured before and 24 hours after the first injection. We conclude that NICHD-Ptxd is immunogenic in children. No serious adverse effects were noted.

History of whooping cough in nonvaccinated Swedish children, related to serum antibodies to pertussis toxin and filamentous hemagglutinin.

The aim of this study was to examine whether there is a correlation between parental information on the child's history of whooping cough and the presence or absence of serum antibodies against two antigens of Bordetella pertussis, pertussis toxin and filamentous hemagglutinin, in nonvaccinated Swedish children. The parents of 266 Swedish children aged 1 to 4 years answered a questionnaire regarding the child's history of whooping cough, and a serum sample was obtained from the child for determination of IgG, IgM, and IgA antibodies to pertussis toxin and filamentous hemagglutinin. The study was performed from 1984 to 1986, five to seven years after the cessation of general vaccination against pertussis in Sweden; none of the children had received pertussis vaccine. Antibodies to both toxin and filamentous hemagglutinin increased with age. Of the children aged 4 years, 50% had antibodies to both antigens. Of all 266 children, 100 had antibodies to both antigens, 6 to toxin alone, and 49 to filamentous hemagglutinin alone. There was a good correlation between the presence of antibodies and a history of whooping cough. Of 91 children with a history of whooping cough, 77 had antibodies against both antigens and 13 against one antigen; only one child lacked detectable antibodies against both antigens. Of the 175 children with no history of whooping cough, 110 lacked detectable antibodies to both antigens, 23 had antibodies to both, 2 to toxin alone, and 40 to filamentous hemagglutinin alone. The data indicate that parental information on a previous history of whooping cough in their nonimmunized child is reliable, and that many infections with B. pertussis are subclinical or atypical. Exposure to other Bordetella species than B. pertussis, which is the only toxin-producing species, might be important for the development of FHA antibodies. A follow-up 2 to 4 years after the collection of serum samples of children without a history of whooping cough but with antibodies to one or both antigens indicated that serum antibodies to toxin, but not to filamentous hemagglutinin, may be protective against disease.

Rapid diagnosis of pertussis.

A rapid and sensitive method has been devised for the detection of Bordetella pertussis in clinical samples. The feasibility of the technique, which is based upon enzymatic assay of adenylate cyclase associated with the intact B. pertussis organisms, has been demonstrated in laboratory simulations. In the present study, we evaluated this novel diagnostic method using clinical specimens obtained from 120 children with suspected pertussis. Levels of adenylate cyclase activity in these specimens were highly correlated with culture results; intermediate and high levels in 28 samples predicted positive cultures in 23 (82%). Further, the adenylate cyclase assay results were obtained 2-7 days earlier than the results of cultures. Among 92 specimens with low levels of adenylate cyclase activity, only 11 were positive in culture. We conclude that adenylate cyclase assays may be suitable for rapid diagnosis of pertussis in children and might facilitate early and effective intervention.

Subclass compositions of immunoglobulin G to pertussis toxin in patients with whooping cough, in healthy individuals, and in recipients of a pertussis toxoid vaccine.

The subclass composition of serum immunoglobulin G (IgG) antibodies against pertussis toxin was studied in 108 serum samples obtained during various stages of disease from 75 patients with whooping cough. IgG1 and IgG3 antibodies were detected in 92 and 42% of the samples, respectively, while only a few contained IgG2 or IgG4 antibodies. Similarly, IgG1 antibodies were predominant in serum samples from healthy children and adults, many of whom had a history of whooping cough several years earlier. Of 85 children and 30 adults with detectable levels of total IgG, 65 and 14 had IgG1 antibodies, respectively, while only 9 of them had IgG3 antibodies. Again, very few sera contained IgG2 or IgG4 antibodies. In contrast, 13 children vaccinated with an acellular aluminum-adsorbed pertussis toxoid vaccine responded mainly with IgG1 and IgG4 antibodies. In conclusion, this study showed that the subclass composition of IgG antibodies to pertussis toxin after natural infection consists mainly of IgG1 and to a certain extent of IgG3, while an aluminum-adsorbed pertussis toxoid induces IgG1 and IgG4 antibodies.