Gunilla Zackrisson

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 Because of its limited efficacy, the Swedish-made whole-cell vaccine was withdrawn in 1979.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.

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.

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.

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.

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 childs 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 childs 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.

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.

Erythromycin-resistant Beta-hemolytic Streptococci Group A in Goteborg, Sweden

A total of 21 erythromycin-resistant strains were found among 355 (5.9%) beta-hemolytic streptococci group A isolated in Göteborg during spring of 1987. T-typing showed 17 to be T12, 1 T4 and 3 nontypable. Spread of resistant strains could be demonstrated within 2 families and 1 day-care-center. Monitoring of erythromycin resistance among beta-hemolytic streptococci is advocated.

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.

Serum antibody response to filamentous hemagglutinin in patients with clinical pertussis measured by an enzyme-linked immunosorbent assay

Titers of antibodies to filamentous hemagglutinin (FHA) were determined by enzymelinked immunosorbent assay in acute and convalescent phase serum samples from 158 patients with clinical symptoms typical of whooping-cough. In 96 of the patients the diagnosis was verified by culture. Significant changes in serum levels of IgG, IgM and/or IgA antibodies against FHA were demonstrated in 126 patients (80%). Thus, demonstration of significant changes in FHA antibody titers in serum can be used for serological diagnosis of pertussis. The results also show that high levels of IgG, IgM and/or IgA antibodies in a single serum sample suggest current pertussis infection, but if the diagnosis is based on determinations of FHA antibody titers in a single serum sample the sensitivity is low. The levels of antibody to FHA were compared with previously determined levels of antibodies to pertussis toxin. A significant antibody response against both FHA and pertussis toxin was seen in 111 patients (70 %) while 147 patients (93 %) developed a significant increase in antibodies against one or both antigens.