Acquisition of IgG serum antibodies against two Bordetella antigens (filamentous hemagglutinin and pertactin) in children with no symptoms of pertussis.

To study the specificity of serum antibodies against filamentous hemagglutinin (FHA) and pertactin for infection with Bordetella pertussis, we followed the acquisition of IgG serum antibodies against these 2 surface proteins of the organism in children who had been vaccinated with a monocomponent pertussis toxoid vaccine and who had experienced no symptoms of pertussis. Antibodies were estimated with enzyme-linked immunosorbent assay. In Part 1 of our study 5 consecutive samples obtained between 3 and 36 months of age from 71 children were available. Most had maternally derived antibodies to FHA (70 of 71) and pertactin (51 of 71) in the 3-month sera which declined in the subsequent sera. From about 1 year of age there were small but significant increases in antibodies against both antigens. At 3 years of age 71 of 71 had antibodies to FHA and 58 of 71 had antibodies to pertactin. In Part 2 of our study sera from 109 three-year old children were available. The 12 children with a history of family exposure to pertussis had significantly higher geometric mean titers of FHA antibodies than the 97 children with no history of family exposure. The geometric mean titers of pertactin antibodies did not differ. We suggest 3 explanations for the acquisition of FHA and pertactin antibodies in children with no history of pertussis: (1) asymptomatic B. pertussis infection in vaccinated children; (2) infection with Bordetella parapertussis; (3) infection with cross-reacting antigens from other organisms, e.g., nonencapsulated Haemophilus influenzae.

Influence of high titers of maternal antibody on the serologic response of infants to diphtheria vaccination at three, five and twelve months of age.

Diphtheria antitoxin was determined in serum from 44 pregnant women, of whom 26 had received one injection of diphtheria toxoid during pregnancy. Their infants were vaccinated with a combined diphtheria-tetanus vaccine at 3, 5 and 12 months of age. This vaccination schedule has been used in Sweden since 1986, replacing the old schedule of vaccination at 3, 4.5 and 6 months of age originally designed for diphtheria-tetanus-pertussis vaccine, which had not been used after cessation of general vaccination against pertussis in 1979. Serum samples from the infants were obtained at 3, 7 and 18 months of age. After 2 injections infants of mothers with high antitoxin titers, > or = 0.1 IU/ml, tended to have lower antitoxin titers than infants of mothers with low antitoxin concentrations (P = 0.067). All children had, however, antitoxin above the minimum protective level of 0.01 IU/ml. Median antitoxin titers were 1.6 IU/ml in both groups after the third booster injection. Four infants of mothers who had been vaccinated during pregnancy and who had titers of > or = 0.4 IU/ml did not reach the 0.1 IU/ml level after 2 injections: all 4 responded with high antitoxin titers after the third dose. Thus all infants were primed by 2 doses of vaccine, irrespective of maternal antibody concentration. The repressive effect of maternal antibody on titers noted after 2 doses was no longer observed after the third, booster dose.

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.

Primum non nocere: a pharmacologically inert pertussis toxoid alone should be the next pertussis vaccine.

The objective of a vaccine for pertussis is to prevent the paroxysmal cough with its complications. Prevention of the paroxysmal cough should prevent transmission of B. pertussis. Clinical studies indicate that a critical level of antitoxin confers protection against pertussis and that the long-lived protective immunity that follows pertussis is best explained by the presence of antitoxin. Vaccine-induced protective immunity can be mediated by a critical level of antitoxin alone. In addition to preventing pertussis with vaccines, we predict this level of antitoxin will also exert epidemiologic control (herd immunity) by inhibition of colonization with B. pertussis and by prevention of the paroxysmal cough which will reduce transmission of this pathogen. Lastly, a pertussis toxoid need not have detectable pharmacologic activity to exert its protective actions: residual activity could exert a deleterious effect on glucose metabolism and exert immunomodulating effects. Accordingly the new pertussis vaccine should contain inactivated pertussis toxoid alone and there is no need to include other components. Several candidates could serve as a satisfactory pertussis toxoid. The admonition to physicians given by Hippocrates, Primum non nocere (first of all do no harm), should be heeded by those responsible for the development and use of the new pertussis vaccine.

Safety, immunogenicity and an open, retrospective study of efficacy of a monocomponent pertussis toxoid vaccine in infants.

One hundred forty-five infants were vaccinated with 25 micrograms of pertussis toxoid (NICHD-Ptxd) at 3, 5 and 7 or at 3, 5 and 12 months of age. One month after the third vaccination all had high serum IgG and neutralizing antibodies (antitoxin) against pertussis toxin. Vaccination at 3, 5 and 12 months resulted in higher antibody titers than vaccination at 3, 5 and 7 months. Sera obtained from 109 children at 3 years of age showed a decline of antibodies, but all had detectable antibodies. Adverse reactions were confined to local redness and swelling, which exceeded 2 cm after 17% of all injections. When the children were 3 years old, a comparison was made of the incidence of clinical pertussis in 142 of the 145 vaccinated children and in 284 age-matched controls living in the same areas. Information on symptoms of pertussis was obtained from the parents during telephone interviews. None of the vaccinated children had clinical pertussis, defined as a 6-week course of paroxysmal cough with whooping attacks or vomiting, whereas 57 controls (20%) had experienced these symptoms. Sixteen vaccinated children were exposed to pertussis in the household. Two of them had laboratory-verified Bordetella pertussis infections with cough of 2 and 4 weeks, respectively, without whooping attacks or vomiting, whereas 14 did not develop a cough. The study shows that NICHD-Ptxd is immunogenic in infants and that it most likely confers a high degree of protection against pertussis.

Immunization of children with pertussis toxoid decreases spread of pertussis within the family.

OBJECTIVE: In a previously reported double blind placebo-controlled trial it was shown that vaccination with pertussis toxoid during infancy reduced the incidence of pertussis in the vaccinees. Parents and siblings of participants in the trial were followed for pertussis to determine whether vaccination provided indirect protection of close contacts in a nonvaccinating country with a high incidence of pertussis. STUDY DESIGN: A group of 3450 infants were randomized to vaccination with diphtheria, tetanus and pertussis toxoids (DTPtxd) or to diphtheria and tetanus toxoids (DT). Pertussis cases were actively sought and diagnosed by cultures and serology in vaccinees (previously reported) and in family members during 2 years after the third vaccination. RESULTS: Pertussis as defined by the World Health Organization (paroxysmal cough of > or = 21 days and certain laboratory criteria) was diagnosed in 11 parents of DTPtxd recipients and in 26 parents of DT recipients; indirect protection was 60% (95% confidence intervals, 16 to 82%). In nonvaccinated younger siblings of DTPtxd and DT recipients there were 10 and 18 cases of pertussis, respectively; indirect protection was 43% (95% confidence intervals, -31 to 76%). When all cases of pertussis with cough > or = 7 days were included, the indirect protection was 44% (95% confidence intervals, 7 to 67%) in parents and 56% (95% confidence intervals, 9 to 81%) in younger siblings. CONCLUSION: Vaccination of children with pertussis toxoid reduces spread of pertussis to close contacts, which suggests that mass vaccination with pertussis toxoid would induce herd immunity.

Persistence of serum antibodies elicited by Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants vaccinated at 3, 5 and 12 months of age.

Eighty-five children received three injections of a vaccine consisting of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) conjugated to tetanus toxoid (TT) (Hib-TT) at 3, 5 and 12 months of age according to the vaccination schedule for Swedish children. Diphtheria-tetanus toxoid vaccine was concurrently injected at another site. Two dosages, 7.5 and 15 micrograms, of Hib CPS were studied. No serious reactions occurred. Hib-TT elicited fewer local reactions than diphtheria-tetanus toxoid vaccine. Significant increases in Hib CPS serum antibodies occurred after all injections in both dosage groups with virtually no differences between the two groups. After the first and second injections geometric mean serum antibody concentrations of both dosage groups combined increased to 0.49 and 3.71 micrograms/ml and 81 and 99% of the vaccinees, respectively, had concentrations greater than 0.15 micrograms/ml. After the third dose geometric mean concentrations increased to 13.7 micrograms/ml and all had concentrations greater than 0.15 micrograms/ml. The geometric mean Hib CPS antibody concentrations decreased to 1.24 micrograms/ml 18 months after the third injection, but 97% still had concentrations greater than 0.15 micrograms/ml. The rise of Hib CPS antibodies was mostly in the IgG class. The most pronounced increase was seen in the IgG1 subclass but there were also increase in IgG2 and IgG3. Protective concentrations of TT antibodies were found in all postimmunization sera. In conclusion Hib-TT is safe and immunogenic in infants and should be protective from 6 to 30 months and probably longer thereafter.

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.

Estimating incidence of whooping cough over time: a cross-sectional recall study of four Swedish birth cohorts.

Incidence of whooping cough was studied in Göteborg, Sweden, in four random samples of birth cohorts from 1972, 1977, 1978 and 1980. To obtain data a postal questionnaire to parents was used and methodologically explored. Vaccination data were taken from health cards. Four years after stopping vaccination cumulative incidence in the unvaccinated cohort born 1980 had risen to levels of the prevaccination era. Sex differences in susceptibility were not seen. Efficacy of the Swedish manufactured non-adsorbed whole cell pertussis vaccine was low. In a developed country like Sweden a cross-sectional study of random samples from the community with recall data may give useful information on the incidence of a disease like whooping cough at a comparatively low cost.

Determination of pertactin IgG antibodies for the diagnosis of pertussis.

OBJECTIVE: To compare increases in serum IgG antibody against pertactin with increases in IgG against pertussis toxin and filamentous hemagglutinin (FHA) in non-vaccinated children, children vaccinated with pertussis toxoid, and adults, all with culture-confirmed pertussis. METHODS: During a double-blind, placebo-controlled, efficacy trial of a monocomponent pertussis toxoid vaccine, acute and convalescent sera were obtained from study children and family members with suspected pertussis. In the present study, IgG antibodies against pertactin, pertussis toxin and FHA (determined by ELISA) were compared in 207 individuals with culture-verified pertussis and paroxysmal cough for >/= 21 days. RESULTS: Significant increases in geometric mean serum IgG against all antigens occurred in non-vaccinated children, but more children responded against pertussis toxin and FHA than against pertactin (96%, 97%, and 62%, respectively). Of the children who had pertussis even though they were vaccinated with the pertussis toxoid vaccine, 97% responded to FHA, while responses to pertussis toxin and pertactin were less common (68% and 61%, respectively). In the 20 adults, the proportions of responders to FHA, pertussis toxin and pertactin were 90%, 80% and 55%, respectively. CONCLUSION: Determination of IgG against pertussis toxin and FHA in paired sera in non-vaccinated children with pertussis is a more sensitive diagnostic tool than determination of IgG against pertactin. Pertactin IgG determinations might be of value as a complement to the other antibody assays in vaccinated children and in adults.

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.

Immunity to pertussis. Not all virulence factors are protective antigens.

As with diphtheria, immunity to pertussis is complex because it involves both individual and community protection against infection with B. pertussis. Although B. pertussis has at least five proteins required for virulence and an additional two "toxic" components, only serum neutralizing antibodies to PT (antitoxin) have been shown to confer immunity to pertussis.

Dental development, dental age and tooth counts.

Emergence data on the 20 deciduous teeth and the first 29 permanent teeth were collected from 212 randomly selected urban Swedish children who were followed from birth to 18 years of age. The sex difference in the emergence of the deciduous teeth is less than one month, which is not statistically significant. Boys are consistently ahead of girls until the 17th deciduous tooth. From the 17th deciduous tooth on through most of the permanent dentition, girls are consistently ahead of boys. In the permanent dentition the sex difference ranges from 3 MO to 11 MO; these differences are statistically significant except for the 29th tooth. Reference data on dental age based on counts of 1-19 deciduous and 1-27 permanent teeth are tabulated and tooth emergence curves constructed. The tooth emergence curves can be used to express individual dental development in terms of standard deviation scores. Validity of dental age assessed by counts of permanent teeth is evaluated by a cross-sectional comparison with another sample of Swedish boys and girls. The mean difference between estimated age and chronological age is about one month in either sex. Precision of an individual estimate of dental development in terms of 95% confidence level (approximately equal to +/- 2 S.D.) varies from about +/- 4 months in the deciduous dentition to +/- 3 years in the permanent dentition. Assessment of dental development and dental age by means of tooth counts is a convenient and simple method, although it can only be applied at ages when emergence can be expected. It is especially useful in cross-sectional evaluations, as no serial data are required. In populations with a low incidence of caries the impact of such disturbing factors on emergence is correspondingly low, further increasing the validity of assessments of dental development based on tooth emergence.

Timing of tooth emergence. A prospective longitudinal study of Swedish urban children from birth to 18 years.

Longitudinal data on tooth emergence were collected from birth to 18 years from 212 randomly selected Swedish urban children. At 18 years, 76 per cent (160/212) of the original subjects were examined. All deciduous teeth except the mandibular second molar emerged earlier in boys than in girls, but the sex difference was only statistically significant (p less than 0.05) for the maxillary laterals and mandibular canines. All permanent teeth emerged significantly earlier in girls than in boys, the sex difference being 2.5 to 14 months.

Pubertal growth and maturity pattern in early and late maturers. A prospective longitudinal study of Swedish urban children.

Pubertal growth in height and the pattern of skeletal and pubertal development were studied in early and late maturers of each sex. The growth rate in height in relation to age at peak height velocity was found to be significantly greater in early maturers of both sexes from at least 7 years before to 2 years after PHV. The peak height was greater in early than in late maturers, the difference being statistically significant in boys only. The amount of growth during the pubertal growth spurt was significantly greater in the early maturers of each sex. The lag periods between the occurrence of maturity indicators of skeletal and pubertal development in relation to age at peak height velocity differed between early and late maturers. The maturity indicators occurred earlier in relation to PHV in the late maturer of each sex.

The timing of secondary sex characters and their relationship to the pubertal maximum of linear growth in girls.

The timing and interrelationships between stages of secondary sex characters and the pubertal maximum of growth were studied in a prospective longitudinal study of 90 Swedish girls, followed from birth to adulthood. The results show that there is a close correlation between some of the stages of secondary sex characters and the pubertal maximum of growth in girls.