John Taranger

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 Because of its limited efficacy, the Swedish-made whole-cell vaccine was withdrawn in 1979.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

Correlation between Pertussis Toxin IgG Antibodies in Postvaccination Sera and Subsequent Protection against Pertussis

All acellular pertussis vaccines contain pertussis toxoid and induce protection against pertussis. This study investigated the relation between the postvaccination levels of pertussis toxin (PT) serum IgG and protection against pertussis. PT IgG was determined in sera obtained 21-77 days after the third vaccination from 813 children who received 3 doses of pertussis toxoid. The children were followed for 21-33 months after vaccination for the occurrence of pertussis. Of the children, 126 were exposed to pertussis in their households. The median PT IgG concentration was 79 U/mL in those who developed severe pertussis (>/=21 day of paroxysmal cough), 156 U/mL with mild pertussis (<21 days of paroxysmal cough), and 246 U/mL in those who did not develop pertussis (79 vs. 246, P<.0001). Corresponding values in the 687 children with no household exposure were 99, 124, and 155 U/mL, respectively (99 vs. 155, P<.0001). Thus, there is a highly significant correlation between the level of vaccine-induced serum PT IgG and protection against pertussis.

Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children.

The safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) alone, or covalently bound to tetanus toxoid in saline solution (Hib-TT) or adsorbed onto AI(OH)3 (Hib-TT ads), were evaluated after one injection into 18- to 23-month-old healthy children in Sweden. No side reactions were elicited by Hib CPS; side reactions elicited by the two conjugates were similar and comparable to those reported for diphtheria and tetanus toxoids adsorbed. Hib-TT was the most immunogenic of the three vaccines, eliciting about 10-fold higher antibody levels than Hib CPS; of 28 vaccinees, all had greater than 1.0 microgram Ab/mL serum after immunization with Hib-TT. Increases of Hib CPS antibodies within immunoglobulin classes induced by the three vaccines were, in decreasing order, IgG greater than IgM greater than IgA. Within IgG subclasses, rises in IgG1 Hib CPS antibodies were the most frequent, followed by IgG2; some vaccinees with high postimmunization levels also had rises in IgG3 and one in IgG4. Immunization-induced Hib CPS antibodies were bactericidal. Hib-TT also elicited higher levels of tetanus toxoid antibodies than Hib-TT ads; these tetanus toxoid antibodies neutralized tetanus toxin in vivo.

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.

Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate*

Bo A. Claesson, MD, Rachel Schneerson, MD, John B. Robbins, MD, Jan Johansson, MD, Teresa Lagerga rd , PhD, John Taranger , MD, Dolores Bryla, MPH, Lily Levi, MSc, Tad Cramton , MS, and Birger Trollfors, MD From the Departments of Infectious Diseases, Pediatrics, and Medical Microbiology, University of Gothenburg, the Department of Pediatrics, Boras Hospital, Pediatric Outpatient Clinic, Vastra Frolunda, Sweden, and the Laboratory of Developmental and Molecular Immunity, and Biometry Branch, National Institute of Child Health and Human DevelopmenL National Institutes of Health, Bethesda, Maryland

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.

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 diphtheriatetanus-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, ≶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 ≶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.

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.

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.

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.