Monocomponent Pertussis Toxoid Vaccine Research Articles

Pertussis after end of a mass vaccination project—End of the “vaccination honey-moon”

After 16 years of no vaccination against pertussis in Sweden, mass vaccination of infants and catch-up vaccination of children up to 10 years with a monocomponent pertussis toxoid vaccine was performed in the Greater Gothenburg area of Sweden between 1995 and 1999. At the end of the project in February 1999, 56% of all 10 year old children born in the Greater Gothenburg area had received 3 doses of the pertussis toxoid. No booster doses were given. This led to a temporary almost complete elimination of the disease. The aim of the present study was to follow the incidence of pertussis after end of the mass vaccination project (1999–2009) as it is reflected by laboratory verified cases (cultures and/or PCR) and pertussis hospitalizations. A reemergence of pertussis was seen from the end of 1999 with a peak in 2004 followed by a decrease when booster doses to both 6 and 10 year old children were introduced in 2005–2006. From July 1, 1999 through December 31, 2009 a total of 1973 cases were diagnosed with culture or PCR. The disease was prevalent in all age groups. The highest documented incidence was seen in infants younger than 12 months. 450 patients with verified pertussis had received 3 doses of the pertussis toxoid vaccine in the mass vaccination project and some other trials (comprising a total of 69,423 children). The mean time from the last dose to the laboratory verification of pertussis was 5 years in these 450 cases. There were 128 hospitalizations, 106 of which were in infants. In conclusion, pertussis is still not eliminated from the area. Booster doses are needed but the numbers and optimal timing are not known.

Determination of pertactin IgG antibodies for the diagnosis of pertussis

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. 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. 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. 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.

Immunologic and epidemiologic experience of vaccination with a monocomponent pertussis toxoid vaccine.

Pertussis re-emerged in Sweden with a cumulative incidence of about 60% during the first 10 years of life, when the locally produced cellular vaccine lost its efficacy around 1970 and general vaccination was discontinued in 1979. The epidemiology, clinical features, and immunology of pertussis and a monocomponent pertussis toxoid vaccine were studied in Göteborg, Sweden. After phase 1 and 2 studies, a randomized, double-blind, placebo-controlled trial of pertussis toxoid (PTox), compounded with diphtheria and tetanus toxoids, was administered to 3450 children according to the Swedish schedule at 3, 5, and 12 months of age. After a mean follow-up of 18 months, the efficacy was 71% overall and 75% in household contacts, respectively. A statistically significant correlation was found between the level of PTox-induced antibodies and protection against pertussis. As observed with cellular and with multicomponent acellular vaccines, PTox reduced the severity of disease and the percent of children with positive cultures. Furthermore, vaccination reduced the transmission of Bordetella pertussis to household contacts in the vaccinees compared with the controls who received only diphtheria and tetanus toxoids. Patients with culture-verified Bordetella parapertussis infection reacted with antibodies to pertactin and to filamentous hemagglutinin but not to pertussis toxin, and some subsequently developed pertussis. The antibody responses of patients with pertussis to the surface polysaccharides of B pertussis and to B parapertussis were cross-reactive serologically. Serosurveys showed that only antibodies to pertussis toxin were related to the occurrence of pertussis in the general population: antibodies to filamentous hemagglutinin and pertactin were probably stimulated by antigens of other bacteria as well as Bordetellae. Mass vaccination of Göteborg children born in the 1990s was started in 1995. In February 1999, about 55% had been vaccinated and both B pertussis and pertussis decreased significantly in individuals of all ages (herd immunity). Similar to diphtheria, PTox-induced immunity to pertussis occurs both on an individual and community basis. The apparent greater efficacy of multicomponent acellular pertussis vaccines compared with monocomponent PTox was proposed to be an artifact created when the diagnosis of pertussis was made by the serologic criteria of the World Health Organization only. Our conclusion is that PTox is both an essential and alone sufficient antigen in acellular pertussis vaccines.

Protection Against Pertussis with a Monocomponent Pertussis Toxoid Vaccine

This study was undertaken to assess the safety and protective efficacy against pertussis of a monocomponent pertussis toxoid vaccine in a society with hyperendemic pertussis. A total of 3450 healthy infants from child health centers in the Goteborg area of Sweden were enrolled in a double-blind, randomized, placebo-controlled study. A combined diphtheria-tetanus vaccine was given with or without pertussis toxoid (DTP-toxoids vs DT-toxoids) at 3, 5, and 12 months of age. One week after each vaccination a telephone interview about reactions was performed. From the day of the first vaccination a nasopharyngeal culture and acute and convalescent sera were obtained from study children and family members with cough lasting 7 or more days. Coughing episodes were classified according to the World Health Organization (WHO) definition of pertussis. There were no serious reactions. There were slightly more local reactions with DTP-toxoids than with DT-toxoids. During the period of blinded follow-up, which began from 30 days after the third vaccination and lasted on average for 17.5 months, the general vaccine efficacy was 71% (95% confidence interval (Cl), 63-78%), and during an extended period of open followup performed during 6 months, vaccine efficacy was 77% (95% Cl, 65-85%). The efficacy against household exposure during the same periods was 73% (95% Cl, 61-83%) and 76% (95% Cl, 51-91%) respectively. A hydrogen-peroxide inactivated pertussis toxoid vaccine that is easily standardized is safe and confers substantial protection against pertussis.

Developing Better Paediatric Vaccines

After 2 decades of development, acellular pertussis vaccines are becoming more widely available for use. Products that contain from 1 to 5 purified antigens of Bordetella pertussis have been assessed in safety, immunogenicity and efficacy studies and are licensed in an increasing number of countries. All acellular pertussis vaccines are associated with fewer local and systemic adverse reactions than the whole-cell pertussis vaccines that have been used for the last 50 years. The acellular pertussis vaccines elicit an antibody response that is generally equivalent to that seen with the whole-cell pertussis vaccines. The acellular pertussis vaccines are effective; using a case-definition of paroxysmal cough of 21 or more days and laboratory confirmation of pertussis, protective efficacy was variable but in excess of 70% for most products. Relative efficacy of the acellular pertussis vaccines and the whole-cell pertussis vaccines was also variable, depending on the products involved and the study design. The choice of antigen content for acellular pertussis vaccines is controversial. Although there are proponents of a monocomponent pertussis toxoid vaccine, the weight of evidence suggests that multicomponent vaccines containing pertussis toxoid and filamentous haemagglutinin and pertactin are more effective than 1- or 2-component vaccines, and that the addition of fimbriae may provide additional protection against less severe disease. Acellular pertussis vaccines are all available in combination with diphtheria and tetanus toxoids; some products also contain inactivated poliovirus vaccine and Haemophilus influenzae b-conjugate vaccine or hepatitis B vaccine. Not all acellular pertussis vaccines are available in these larger combinations because of difficulties with decreased antibody response to one or more antigens in the combined product. Future directions for research into acellular pertussis vaccines include optimisation of antigen content and administration schedule, and further development of multicomponent vaccines.

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 doses 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. (J Pediatr 1997;130:532-6)

Protection against pertussis with a monocomponent pertussis toxoid vaccine

This study was undertaken to assess the safety and protective efficacy against pertussis of a monocomponent pertussis toxoid vaccine in a society with hyperendemic pertussis. A total of 3450 healthy infants from child health centers in the Göteborg area of Sweden were enrolled in a double-blind, randomized, placebo-controlled study. A combined diphtheria-tetanus vaccine was given with or without pertussis toxoid (DTP-toxoids vs DT toxoids) at 3, 5, and 12 months of age. One week after each vaccination a telephone interview about reactions was performed. From the day of the first vaccination a nasopharyngeal culture and acute and convalescent sera were obtained from study children and family members with cough lasting 7 or more days. Coughing episodes were classified according to the World Health Organization (WHO) definition of pertussis. There were no serious reactions. There were slightly more local reactions with DTP-toxoids than with DT-toxoids. During the period of blinded follow-up, which began from 30 days after the third vaccination and lasted on average for 17.5 months, the general vaccine efficacy was 71% (95% confidence interval (Cl), 63–78%), and during an extended period of open followup performed during 6 months, vaccine efficacy was 77% (95% Cl, 65–85%). The efficacy against household exposure during the same periods was 73% (95% CI, 61–83%) and 76% (95% Cl, 51–91%), respectively. A hydrogen-peroxide inactivated pertussis toxoid vaccine that is easily standardized is safe and confers substantial protection against pertussis.

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.

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.

Pertussis Antibodies, Protection, and Vaccine Efficacy After Household Exposure

During a randomized trial of a cellular pertussis vaccines, significantly fewer recipients of a two-component vaccine (Japanese National Institute of Health [JNIH]-6) were diagnosed as primary or coprimary cases in households than either placebo recipients or those who received a monocomponent pertussis toxoid vaccine (JNIH-7). After household exposure to a culture-confirmed primary case, efficacy for JNIH-6 was estimated to be 35% (95% confidence interval, -14% to 57%) against any culture-confirmed disease and 58% (95% confidence interval, -6% to 84%) against clinical disease with 21 days or more of coughing spasms. The corresponding efficacy estimates for JNIH-7 were 67% (95% confidence interval, 32% to 80%) and 82% (95% confidence interval, 41% to 96%). Differences between the JNIH-6 and JNIH-7 vaccines in efficacy after household exposure were not statistically significant. No association could be established between protection against pertussis after household exposure and serum levels of IgG antibody to pertussis toxin or filamentous hemagglutinin in vaccinated individuals, in either study children or other household members.

Specific immunoglobulin for treatment of whooping cough

Immunoglobulin treatment for whooping cough (pertussis) is widely believed to be ineffective although there are sound reasons for regarding the condition as a toxin-induced disease. We wondered whether the lack of success with pertussis immunoglobulins might be attributable to inadequate dose, so we designed a randomised, double-blind, placebo-controlled trial of two immunoglobulin preparations. The study was conducted at three Swedish hospitals. We enrolled 73 children aged less than 36 months who were admitted with a clinical diagnosis of whooping cough. On admission they were assigned to one of three groups: (a) monocomponent pertussis toxoid vaccine; (b) two-component acellular vaccine also containing filamentous haemagglutinin; or (c) 20% albumin solution (placebo). The immunoglobulins had a high antitoxin content and had been raised with acellular pertussis vaccines. Diagnosis of pertussis was confirmed by laboratory tests and the follow-up was completed in 67 children. The main study group consisted of 47 children with ≤ 14 days of disease before therapy. Duration of whoops post-treatment was 8·7 days (95% Cl 4·8, 12·6) in the 33 children receiving immunoglobulin vs 20·6 (95% Cl 11·9, 29·3) in the 14 receiving placebo (p=0·0041). Mean number of whoops during the first week of follow-up was also significantly reduced (p=0·0196). We found that early treatment was important, since the effect on duration of whoops was most pronounced when disease duration before treatment was ≤7 days. There were no significant differences between the two immunoglobulin preparations. High-dose specific pertussis immunoglobulin with a high antitoxin concentration has a beneficial effect in the treatment of whooping cough.

Circumscribed edema in the nursling: Zerbino, V.: Arch. de pediat. d. Uruguay 12: 354, 1941

This study was undertaken to assess the safety and protective efficacy against pertussis of a monocomponent pertussis toxoid vaccine in a society with hyperendemic pertussis. A total of 3450 healthy infants from child health centers in the Göteborg area of Sweden were enrolled in a double-blind, randomized, placebo-controlled study. A combined diphtheria-tetanus vaccine was given with or without pertussis toxoid (DTP-toxoids vs DT toxoids) at 3, 5, and 12 months of age. One week after each vaccination a telephone interview about reactions was performed. From the day of the first vaccination a nasopharyngeal culture and acute and convalescent sera were obtained from study children and family members with cough lasting 7 or more days. Coughing episodes were classified according to the World Health Organization (WHO) definition of pertussis. There were no serious reactions. There were slightly more local reactions with DTP-toxoids than with DT-toxoids. During the period of blinded follow-up, which began from 30 days after the third vaccination and lasted on average for 17.5 months, the general vaccine efficacy was 71% (95% confidence interval (Cl), 63–78%), and during an extended period of open followup performed during 6 months, vaccine efficacy was 77% (95% Cl, 65–85%). The efficacy against household exposure during the same periods was 73% (95% CI, 61–83%) and 76% (95% Cl, 51–91%), respectively. A hydrogen-peroxide inactivated pertussis toxoid vaccine that is easily standardized is safe and confers substantial protection against pertussis.