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Comparative study of the reactogenicity of a three-component acellular pertussis vaccine and whole-cell pertussis vaccine administered to healthy Singaporean infants
Abstract
The objective of this study was to assess and compare the reactogenicity of GlaxoSmithKline (GSK) Biologicals' diphtheria-tetanus-tricomponent acellular pertussis vaccine (DTPa) and the locally used combined diphtheria-tetanus-whole-cell pertussis vaccine (DTPw) as a primary vaccination course in healthy infants at the age of 3, 4 and 5 months. A phase IV, single-blinded, randomized comparative clinical study involved one hundred and eighty healthy infants with two study groups in a 2:1 ratio to receive either DTPa or DTPw vaccine which were administered intramuscularly at the right anterior-lateral aspect of the thigh. The incidence and intensity of local solicited symptoms such as pain, redness and swelling at injection site and general solicited symptoms such as fever and fussiness were evaluated. Serious adverse events were followed for one month after each vaccination. The overall incidence of local and general symptoms was significantly higher in the group receiving locally used DTPw vaccine as compared to the group receiving GSK DTPa vaccine. Solicited local symptoms, pain (47.4% vs 15.1%), redness (95.9% vs 84.9%) and swelling (46.2% vs 18.5%), were reported more frequently in the group receiving DTPw vaccine than in the group receiving DTPa vaccine. Fever (> or = 37.5 degrees C) (52% vs 14.6%) and fussiness (60.8% vs 33.6%) were also more commonly reported in the DTPw group. There were six serious adverse events reported (4 with DTPw and 2 with DTPa). None of them related to the study vaccines, as considered by the investigators. Thus it was found that GSK Biologicals' DTPa vaccine was significantly less reactogenic as compared to the locally used DTPw vaccine manufactured by Commonwealth Serum Laboratories when administered as a 3-dose primary vaccination course to healthy infants at the age of 3, 4 and 5 months in Singapore.
... Acellular pertussis vaccines have now been evaluated in adolescents and adults and confer safe and effective protection against pertussis, 14 also as combination vaccine together with tetanus and diphtheria (Tdap). 16,17 In a large prospective study in the United States using the tricomponent acellular pertussis vaccine, the vaccine protection was 92%. 8 As adult travelers often require a booster for tetanus and diphtheria prior to their travel, this is an opportunity to offer the combined vaccine for adult tetanus, diphtheria, and acellular pertussis. ...
Introduction Pertussis is a worldwide, highly communicable, vaccine-preventable respiratory disease and is a frequent but often underestimated cause of prolonged cough illness in adults. Immunity from childhood pertussis immunization is thought to last only up to 10 years. The incidence of adult pertussis has been estimated to be 200 to 500 per 100,000 persons-years. Acellular pertussis vaccines have been evaluated in adults and confer safe and effective protection and now exist as combination vaccine together with tetanus and diphtheria.
Methods We did a questionnaire survey to assess the knowledge, attitude, and practices toward pertussis in adult travelers. We consecutively enrolled all travelers who presented at the Travellers’ Health & Vaccination Centre in Singapore in 1 month.
Results Of 218 consecutively enrolled travelers, 184 (84.4%) completed the questionnaire; of which 80% were Singaporeans. Seventy persons (38%) did not know or gave a wrong answer for the mode of transmission of pertussis, 147 (83%) had never heard of a pertussis vaccine for adults, and almost none had received an adult pertussis vaccine booster. Travelers from Western countries were seven times [95% confidence interval (CI): 2—27] more likely than Asians to have knowledge about pertussis; women were 4.27 times (95% CI: 1.59–11.53) more likely than men to be aware of the booster vaccine, after adjusting for nationality ( p= 0.004).
Conclusions Knowledge about pertussis was poor among adult travelers. Although pertussis was viewed as a serious illness by the majority of participants, and 38% expressed the desire to be vaccinated, almost no one had received the pertussis vaccine booster. Awareness about pertussis, its risks, and prevention via vaccination need to be increased among adult travelers. Studies are needed to quantify the risk of pertussis in adult travelers.
... The vaccines have been widely used from 1984 4) and are considered effective in preventing pertussis disease in the country. Acellular pertussis vaccines have an improved tolerability profile compared to whole cell pertussis (DTPw) vaccines 5,6) . In Korea, after the transition from DTPw to DTPa, the five-dose coverage rates for DTPa (three primary doses and two booster doses) rose from 65% to 81% between 2004 and 2007 7) , correlating with improved diphtheria, tetanus and pertussis disease control 8) . ...
Purpose : To compare immunogenicity and reactogenicity of a combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (DTPa-IPV, InfanrixTM IPV, GlaxoSmithKline Biologicals) with co-administration of commercially available DTPa and IPV vaccines at separate injection sites (DTPa+IPV). Methods : A total of 458 infants aged 8-12 weeks were randomized to receive three-dose primary vaccination at 2, 4 and 6 months with DTPa-IPV or DTPa+IPV. Blood samples were collected pre and post vaccination for measurement of immune responses. Reactogenicity was assessed following each dose using diary cards. Results : One month post-dose 3, seroprotection rates for anti-diphtheria, anti-tetanus and anti-poliovirus types 1, 2 and
3 were ≥99.5% and vaccine response rates to pertussis antigens were at least 98.6% in both DTPa-IPV and DTPa + IPV groups. Non-inferiority between the groups was demonstrated based on pre-defined statistical criteria. Incidences of both local and systemic symptoms were within the same range across both groups with grade 3 symptoms reported following no more than 4.3% of DTPa-IPV doses and 4.5% of DTPa + IPV doses. Two serious adverse events (both pyrexia) after DTPa-IPV administration were considered vaccine-related. Both infants recovered fully. Conclusion : Combined DTPa-IPV vaccine was immunogenic and well tolerated when used as a three-dose primary vaccination course in Korean infants. DTPa-IPV could be incorporated into the Korean vaccination schedule, reducing the number of injections required to complete primary immunization. (Korean J Pediatr Infect Dis 2010;17:156-168)
... A significant number of parents choose instead to pay to immunise their children with combined acellular pertussis vaccines also available in Singapore. The features of combined diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis-Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) that appeal to parents and practitioners include: fewer adverse reactions after vaccination compared to whole-cell pertussis preparations, 5 the inclusion of IPV, thereby avoiding the rare but potentially devastating complication of vaccine-associated paralytic polio associated with the use of oral polio vaccines; the inclusion of Hib protection; and finally but perhaps of most vaccination reduces the number of injections required at each visit, an additional injection with HBV continues to be needed at either the fifth or sixth month when infants receive their final HBV immunisation. The combined hexavalent DTPa-HBV-IPV/Hib vaccine builds on the features of DTPa-IPV/Hib, with the additional inclusion of HBV in the vaccine formulation. ...
Children in Singapore receive vaccination against hepatitis B virus (HBV) at 0, 1 and 5 or 6 months of age, and vaccination against pertussis, diphtheria, tetanus, and polio at 3, 4 and 5 months of age. Parents often choose to vaccinate with the combined acellular-pertussis-inactivated polio-Hib vaccine (DTPa-IPV/Hib). We investigated whether a combined hexavalent vaccine, DTPa-HBV-IPV/Hib, could replace the separate administration of DTPa-IPV/Hib and HBV for the final vaccination at 5 months of age (Trial DTPa-HBV-IPV-075).
In an open study, 150 children were randomised to complete their vaccination schedule with DTPa-IPV/Hib + HBV or DTPa-HBV-IPV/Hib.
One month after the final vaccination, there was no difference between groups in seroprotection rates or antibody concentrations against HBV. Seroprotection rates against diphtheria, tetanus, Hib and polio, as well as vaccine response rates to pertussis antigens were also similar between groups. Local and general symptoms occurred at a similar rate after the third dose of either vaccine.
The immunogenicity and reactogenicity of the hexavalent vaccine DTPa-HBV-IPV/Hib (Infanrix hexa, GSK) group is comparable to that of separately administered DTPa-IPV/Hib and HBV vaccines. Combined hexavalent vaccine, DTPa-HBV-IPV/Hib, could replace the separate administration of DTPa-IPV/Hib and HBV for vaccination at 5 months of age, thereby reducing the number of injections required.
Purpose
– The purpose of this paper is to provide a review of the literature on pertussis immunisations among the Asian population.
Design/methodology/approach
– A systematic review was carried out using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review performed searches using the keywords: immun*, vaccine* AND whooping cough or Bordetella pertussis OR B pertussis AND Asia*. The search was conducted on four electronic databases, namely, Medline, CINAHL, Embase and Cochrane Database of Systematic Reviews.
Findings
– In total, 13 studies of relevance were included in the review after screening 206 articles. The studies were categorised into three literature sections which were: epidemiology of pertussis, vaccine effectiveness studies in Asia and strategies aimed to increase uptake of immunisations against pertussis.
Research limitations/implications
– Due to financial constraints, the authors only had access to articles published in the English language and full text articles which may limit the generalisability of the review.
Originality/value
– The review is useful in providing insight into the general trends of pertussis immunisations among Asians and in aiding future research in this area.
The authors have no financial or other potential conflicts of interest to disclose.
The aim of the study is to evaluate the level of antibodies against pertussis toxin in a sample of vaccinated children in relation to the recent changes in the vaccination scheme in the Czech Republic. In 122 children born in 2000-2006, the level of IgG antibodies against pertussis toxin was examined using the ELISA method. These children received at least three doses of the vaccine, more than four weeks prior to blood collection. The type of the vaccine and the period of time after the last vaccination were observed. In the whole sample of vaccinated children, who received at least three doses of the vaccine, only 37 had a positive level of antibodies in the time period of 1-42 months after the last vaccination. The difference between the whole-cell vaccine and the acellular vaccine was not statistically significant. The period of time after the last vaccination was in inverse proportion to the number of children with a positive level of antibodies. With regard to the increasing incidence of pertussis in the Czech Republic it would be rewarding to initiate a discussion about the booster dose with the acellular vaccine against pertussis at the age of 9-14 years.
Background:
In Turkey, several changes have been made in the vaccination schedule. Vaccines against diphtheria, tetanus, pertussis and poliomyelitis were applied as DTwP and OPV until the end of 2006. Hib vaccine was added to the schedule and was administered as a separate injection in 2007 as DPT + OPV + Hib. DTaP-IPV/Hib combined vaccine replaced them in 2008. The aim of this study was to evaluate the alterations in the frequency of adverse reactions of these different schedules in the consecutive three years.
Methods:
A total of 2401 infants who were vaccinated in Gazi University Well Child Clinics during the first 3 months of each schedule were enrolled in the study. Local and systemic adverse events were recorded in diaries by the parents for the next three days.
Results:
No significant differences existed between infants vaccinated with DPT + OPV and DPT + OPV + Hib regarding all adverse events detected. Frequency of local and systemic reactions were lower in infants vaccinated with DTaP-IPV/Hib combined vaccine (p < 0.001). Frequency of adverse events in infants vaccinated with DPT + OPV or DPT+ OPV + Hib were highest at booster doses.
Conclusions:
The original experience of the study is the demonstration of the adverse event profile for three different schedules which allowed us to draw the profile of the adverse events in a country with changing national schedules. Implementation of Schedule 3 reduced the adverse events of vaccination. Thus reduction in the number of injections and reactogenicity of pertussis vaccine contributed to an increase in the compliance to the vaccination program.
Background:
Routine use of whole-cell pertussis (wP) vaccines was suspended in some countries in the 1970s and 1980s because of concerns about adverse effects. Following such action, there was a resurgence of whooping cough. Acellular pertussis (aP) vaccines, containing purified or recombinant Bordetella pertussis (B. pertussis) antigens, were developed in the hope that they would be as effective, but less reactogenic than the whole-cell vaccines.
Objectives:
To assess the efficacy and safety of acellular pertussis vaccines in children.
Search methods:
We searched the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4) which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to December week 4, 2011), EMBASE (1974 to January 2012), Biosis Previews (2009 to January 2012), and CINAHL (2009 to January 2012).
Selection criteria:
We selected double-blind randomised efficacy and safety trials of aP vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases.
Data collection and analysis:
Two review authors independently extracted data and assessed the risk of bias in the studies. Differences in trial design precluded a meta-analysis of the efficacy data. We pooled the safety data from individual trials using a random-effects meta-analysis model.
Main results:
We included six efficacy trials with a total of 46,283 participants and 52 safety trials with a total of 136,541 participants. Most of the safety trials did not report the methods for random sequence generation, allocation concealment and blinding, which made it difficult to assess the risk of bias in the studies. The efficacy of multi-component (≥ three) vaccines varied from 84% to 85% in preventing typical whooping cough (characterised by 21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis), and from 71% to 78% in preventing mild pertussis disease (characterised by seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology). In contrast, the efficacy of one- and two-component vaccines varied from 59% to 75% against typical whooping cough and from 13% to 54% against mild pertussis disease. Multi-component acellular vaccines are more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with aP vaccines than with wP vaccines for the primary series as well as for the booster dose.
Authors' conclusions:
Multi-component (≥ three) aP vaccines are effective and show less adverse effects than wP vaccines for the primary series as well as for booster doses.
Background:
Routine use of whole-cell pertussis (wP) vaccines was suspended in some countries in the 1970s and 1980s because of concerns about adverse effects. Following this action, there was a resurgence of whooping cough. Acellular pertussis (aP) vaccines, containing purified or recombinant Bordetella pertussis (B. pertussis) antigens, were developed in the hope that they would be as effective, but less reactogenic than the whole-cell vaccines. This is an update of a Cochrane review first published in 1999, and previously updated in 2012. In this update, we included no new studies.
Objectives:
To assess the efficacy and safety of acellular pertussis vaccines in children and to compare them with the whole-cell vaccines.
Search methods:
We searched CENTRAL (2013, Issue 12), MEDLINE (1950 to January week 2, 2014), EMBASE (1974 to January 2014), Biosis Previews (2009 to January 2014) and CINAHL (2009 to January 2014).
Selection criteria:
We selected double-blind randomised efficacy and safety trials of aP vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases.
Data collection and analysis:
Two review authors independently extracted data and assessed the risk of bias in the studies. Differences in trial design precluded a meta-analysis of the efficacy data. We pooled the safety data from individual trials using a random-effects meta-analysis model.
Main results:
We included six efficacy trials with a total of 46,283 participants and 52 safety trials with a total of 136,541 participants. Most of the safety trials did not report the methods for random sequence generation, allocation concealment and blinding, which made it difficult to assess the risk of bias in the studies. The efficacy of multi-component (≥ three) vaccines varied from 84% to 85% in preventing typical whooping cough (characterised by 21 or more consecutive days of paroxysmal cough with confirmation of B. pertussis infection by culture, appropriate serology or contact with a household member who has culture-confirmed pertussis), and from 71% to 78% in preventing mild pertussis disease (characterised by seven or more consecutive days of cough with confirmation of B. pertussis infection by culture or appropriate serology). In contrast, the efficacy of one- and two-component vaccines varied from 59% to 78% against typical whooping cough and from 41% to 58% against mild pertussis disease. Multi-component acellular vaccines are more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with aP vaccines than with wP vaccines for the primary series as well as for the booster dose.
Authors' conclusions:
Multi-component (≥ three) aP vaccines are effective in preventing whooping cough in children. Multi-component aP vaccines have higher efficacy than low-efficacy wP vaccines, but they may be less efficacious than the highest-efficacy wP vaccines. Acellular vaccines have fewer adverse effects than whole-cell vaccines for the primary series as well as for booster doses.
In recent years, acellular pertussis combination vaccines have facilitated compliance with and coverage of the national immunisation programme in Singapore. This phase-II study (Rota-007) evaluated the immunogenicity, reactogenicity and safety of a DTPa-IPV/Hib combined vaccine when co-administered with a rotavirus vaccine.
A total of 2464 children aged 3 months were vaccinated with DTPa-IPV/Hib together with a randomised 1:3 ratio of either placebo (n=653) or 1 of 3 different formulations of a rotavirus vaccine. Blood samples were collected for immunogenicity analysis 1 month after the third DTPa-IPV/Hib vaccine dose in a subset of subjects (n = 640). Local and general reactogenicity and unsolicited adverse events were recorded during the follow-up after each vaccination.
Serological analysis showed >95% response for all antigens in the co-administered DTPa-IPV/Hib vaccine, with no difference between the rotavirus vaccine and placebo groups. No differences in adverse events and reactogenicity were reported in the rotavirus vaccine and placebo groups. Only 0.2% of the subjects reported Grade 3 adverse events. Three subjects (from the vaccine groups) died during the study, which were assessed by the investigators as unrelated to vaccination. No deaths were reported in the placebo group.
The combined DTPa- IPV/Hib vaccine is safe, well tolerated and highly immunogenic when given alone or coadministered with the rotavirus vaccine for infants in Singapore.
Pertussis, a highly contagious disease caused by Bordetella pertussis, is making a comeback globally despite good immunization coverage. The developed countries have also shown a shift in the epidemiology of the disease to the adolescent and the adult age group, leading to a revision of their vaccination policies. The disease epidemiology in the South East Asian region seems poised for a similar change. Outbreaks have been reported among children and adults in countries such as Afghanistan, Israel, and Taipei. The anticipation and early recognition of this change in the epidemiology is important because the affected adolescents and adults act as reservoirs of the disease to the vulnerable population of infants, for whom the disease can be life threatening. The clinical presentation can be atypical in the adolescent age group, and the disease is often misdiagnosed. With the availability of polymerase chain reaction and serology, the disease can be diagnosed even later in the course of the disease when culture results are often negative. The whole-cell pertussis vaccine dramatically reduced the incidence of the disease but fell into disrepute due to the rare serious neurologic side effects that led to the introduction of the acellular pertussis vaccine, which led to fewer adverse reactions and also proved to be safe and effective in the adolescent age group when used as a booster. However, the cost of the acellular vaccine is may be prohibitive for widespread use in the developing nations of the South East Asian region.
Routine use of whole cell pertussis vaccines was suspended in some countries in the late 1970s and early 1980s, leading to a resurgence of whooping cough. Acellular pertussis vaccines containing purified or recombinant Bordetella pertussis antigens were developed in the hope that they would be as effective but less toxic than the whole cell vaccines.
The objective of this review was to assess the effects of acellular pertussis vaccines in children.
The Cochrane Controlled Trials Register and Medline were searched up to January 1998.
Double-blind randomised efficacy and safety trials of acellular pertussis vaccines in children, with active follow-up of participants and laboratory verification of pertussis cases.
One reviewer assessed trial quality and extracted data.
Six efficacy trials and 45 safety trials were included. Acellular pertussis vaccines with three or more pertussis vaccines were more effective than those with one or two antigens. They were also more effective than one type of whole cell pertussis vaccine, but less effective than two other types of whole cell vaccines. Differences in trial design precluded pooling of the efficacy data and results should be interpreted with caution. Most systemic and local adverse events were significantly less common with acellular than with whole cell pertussis vaccines.
Multi-component acellular pertussis vaccines are effective, and show less adverse effects than whole cell pertussis vaccines. However in areas where whooping cough is more likely to be fatal, the higher toxicity of some whole cell vaccines may be offset by their increased effectiveness.
Cells of Bordetella pertussis BP353, a nonfimbriated Eldering serotype 1.3 strain, were used as an immunogen to produce three monoclonal antibodies, BPE3, BPD8, and BPE8, that agglutinated the immunizing cells, as well as certain other nonfimbriated and fimbriated serotype 3-containing B. pertussis strains. The antibodies did not agglutinate serotype 1 or nontypable B. pertussis cells. These monoclonal antibodies specifically detected a 69-kilodalton (kDa) band on Western blots (immunoblots) containing whole B. pertussis cell lysates of Eldering agglutinogen serotypes 1.3, 1.3.6, 1.2.3.4, and 1.2.3.4.6. This 69-kDa antigen was released from the bacteria by cell incubation for 60 min at 60 degrees C, and it was purified by affinity chromatography with a BPE3-agarose affinity matrix. Purified material was used to produce a polyclonal antiserum that agglutinated all nonfimbriated and fimbriated B. pertussis cells containing serotype 3 agglutinogen. Immunogold electron microscopy and indirect immunofluorescence studies demonstrated that it is an outer membrane constituent but nonfimbrial in appearance. BPE3 did not detect purified fimbriae on Western blots, and antibodies to these fimbriae did not bind to the 69-kDa component. Although B. bronchiseptica and B. parapertussis cells were not agglutinated by the monoclonal antibodies, antigenically similar proteins were detected in extracts of the bacteria. These results identify the 69-kDa protein as a nonfimbrial agglutinogen present on all virulent strains of B. pertussis. The monoclonal antibodies described here should be useful for further studies on the structure and function of this protein.
Concern about both safety and efficacy has made the use of whole-cell pertussis vaccines controversial. In some European countries, including Italy, the rate of vaccination against pertussis is low.
We conducted a double-blind trial in Italy in which infants were randomly assigned to vaccination at two, four, and six months of age with an acellular pertussis vaccine together with diphtheria and tetanus toxoids (DTP); a DTP vaccine containing whole-cell pertussis (manufactured by Connaught Laboratories); or diphtheria and tetanus toxoids without pertussis (DT). The acellular DTP vaccine was either one containing filamentous hemagglutinin, pertactin, and pertussis toxin inactivated with formalin and glutaraldehyde (SmithKline Beecham) or one with filamentous hemagglutinin, pertactin, and genetically detoxified pertussis toxin (Chiron Biocine). Pertussis was defined as 21 days or more of paroxysmal cough, with infection confirmed by culture or serologic testing.
The efficacy of each vaccine, given in three doses, against pertussis was determined for 14,751 children over an average of 17 months, with cases included in the analysis if cough began 30 days or more after the completion of immunization. For both of the acellular DTP vaccines, the efficacy was 84 percent (95 percent confidence intervals, 76 to 89 percent for Biocine DTP and 76 to 90 percent for SmithKline DTP), whereas the efficacy of the whole-cell DTP vaccine was only 36 percent (95 percent confidence interval, 14 to 52 percent). The antibody responses were greater to the acellular vaccines than to the whole-cell vaccine. Local and systemic adverse events were significantly more frequent after the administration of the whole-cell vaccine. For the acellular vaccines, the frequency of adverse events was similar to that in the control (DT) group.
The two acellular DTP vaccines we studied were safe, immunogenic, and efficacious against pertussis, whereas the efficacy of the whole-cell DTP vaccine was unexpectedly low.
A tricomponent acellular pertussis vaccine containing pertussis toxoid, filamentous hemagglutinin, and pertactin combined
with diphtheria and tetanus toxoids (DTPa) was developed as a less reactogenic alternative to the traditional whole cell pertussis
(DTPw) vaccine. In studies of DTPa as a primary vaccination and as a booster dose in DTPa- or DTPw-primed children, the vaccine
was safe, well-tolerated, and highly immunogenic; it was less reactogenic than DTPw but at least as immunogenic. A three-dose
primary vaccination sequence with DTPa vaccine in the first 6 months of life protects against pertussis under conditions of
high infectious pressure. These results support the licensing of the vaccine for primary and booster vaccination in a growing
number of countries. Combined DTPa-based pediatric vaccines are in clinical development.
In 1992-1993, a randomized, double-blind, placebo-controlled clinical trial of two 3-component acellular pertussis vaccines was started in 4 of Italy's 20 regions. During the trial, the children had been randomized to receive 3 doses of 1 of 2 acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DT) or of a DT vaccine only, at 2, 4, and 6 months of age. Both diphtheria-tetanus-acellular pertussis (DTaP) vaccines, 1 manufactured by SmithKline Beecham (DTaP SB; Infanrix) and 1 manufactured by Chiron Biocine (DTaP CB; Triacelluvax), contain pertussis toxin (PT), filamentous hemagglutinin, and pertactin. The results of the first period of follow-up, which ended in 1994 (stage 1), showed that both vaccines had a protective efficacy of 84% in the first 2 years of life; when the trial's follow-up was extended under partial blinding until the participating children had reached 33 months of age (stage 2 of the follow-up), these high levels of efficacy had persisted. Therefore, the objective of this study was to estimate the persistence of protection from 3 to 6 years of age of the 2 3-component DTaP vaccines administered as primary immunization in infancy.
An unblinded prospective longitudinal study of vaccinated and unvaccinated children in 4 Italian regions, with active surveillance of cough, was conducted by study nurses, and Bordetella pertussis infections were confirmed laboratory. The present study (stage 3) included those children who completed stage 2 of the follow-up and were still under active surveillance as of October 1, 1995, accounting for 4217 children who had received DTaP SB (representing 94% of the vaccine's recipients in the initial phase of the trial), 4215 who had received DTaP CB (95% of the original recipients), and 266 who had received DT only (18% of the original recipients). Because the parents of most of the original DT placebo group accepted pertussis vaccination during stage 2 in 1995, an additional 856 children were recruited in the DT group at the initiation of stage 3. These additional children were identified from the census list of children born in the same period and living in the same areas as the trial participants but who had been vaccinated in infancy with DT only. Eligible children were included in stage 3 if they had no history of either pertussis or pertussis vaccination and if a serum sample obtained at the time of enrollment had undetectable immunoglobulin G (IgG) against PT. Parental consent to participate in the study was obtained. Active surveillance for pertussis was conducted in the field by 72 study nurses through monthly contact with each family in the study. A cough episode that lasted >/=7 days was considered to be a laboratory-confirmed infection by Bordetella pertussis if at least 1 of the following 5 criteria (listed in hierarchic order) was met: 1) B pertussis was obtained from nasopharyngeal culture (culture-confirmed infection); 2) the enzyme-linked immunosorbent assay (ELISA) IgG or IgA titer against PT in the convalescent-phase serum sample increased by at least 100% compared with the acute-phase sample; 3) the PT-neutralizing titers in Chinese hamster ovary assay in the convalescent-phase sample increased by at least 4-fold compared with the acute-phase sample; 4) the ELISA IgG or IgA titer against filamentous hemagglutinin in the convalescent-phase sample increased by at least 100% and the culture or the polymerase chain reaction assay on the nasopharyngeal aspirate was negative for B parapertussis; and 5) the ELISA IgG PT titer in 1 of the 2 serum samples exceeded the geometric mean titer computed on convalescent sera of the children with a culture-confirmed B pertussis infection in each study group. Incidence of laboratory-confirmed B pertussis infection, using case definitions that varied in terms of duration and type of cough, was computed and the proportion of cases prevented among DTaP recipients in comparison with DT recipients was calculated.
A total of 391 laboratory-confirmed infections were identified in the 3-year follow-up period (138 DTaP SB, 126 DTaP CB, 127 DT recipients, respectively). The mean duration of cough in children with laboratory-confirmed infection was 48, 47, and 70 days for the DTaP SB, DTaP CB, and DT recipients, respectively; the mean duration of spasmodic cough was 15, 13, and 23 days, respectively. When using the primary case definition (ie, laboratory-confirmed B pertussis infection and >/=14 days of spasmodic cough or >/=21 days of any cough), the efficacy was 78% for the DTaP SB vaccine (95% confidence interval [CI]: 71%-83%) and 81% for the DTaP CB vaccine (95% CI: 74%-85%). When using the case definition based on a more severe clinical presentation (>/=21 days of spasmodic cough), the vaccine efficacy was 86% (95% CI: 79%-91%) for both vaccines. When using the case definition based on milder clinical presentation (any cough for >/=7 days), the efficacy was 76% (95% CI: 69%-81%) for the DTaP SB vaccine and 78% (95% CI: 72%-83%) for the DTaP CB vaccine.
The persistence of protection through 6 years of age suggests that the fourth DTaP dose could be postponed until preschool age in children who received 3-component acellular pertussis vaccines in infancy, provided that immunity to diphtheria and tetanus is maintained. Additional booster doses could be administered at older ages to reduce reactogenicity induced by multiple administrations and to optimize the control of pertussis in adolescents and young adults.
Objective: To determine the impact of the introduc- tion of acellular pertussis vaccine for the fourth and fifth doses of the diphtheria and tetanus toxoids and pertussis vaccine series in children on rates of reported vaccine-associated adverse events in the United States. Design: Analysis of postmarketing vaccine adverse event data from the Vaccine Adverse Event Reporting System during the years 1991 to 1993. Population Studied: Approximately 27 million doses of diphtheria and tetanus toxoids and pertussis vaccine and 5 million doses of diphtheria and tetanus toxoids and acellular pertussis vaccine were distributed from 1991 to 1993 to children 15 months to 7 years of age. Main Outcome Measures: Rates of reported fever, sei- zures, and hospitalizations after pertussis vaccination. Results: Rates of reported adverse events per 100 000 vac- cinations were significantlylower after administration ofdiph- theria and tetanus toxoids and acellular pertussis vaccine than diphtheria and tetanus toxoids and pertussis vaccine for the following outcomes: all reports, 2.9 vs 9.8; fever, 1.9 vs 7.5; seizures, 0.5 vs 1.7; and hospitalizations, 0.2 vs 0.9. Conclusions: These results confirm that minor ad- verse events are less frequent after administration of the acellular pertussis vaccine. In addition, these data sug- gested that seizures and hospitalizations associated with pertussis vaccination are less frequent after administra- tion of the acellular pertussis vaccine in age groups for which it is now recommended.
Five hundred and fifty-seven infants received either an acellular pertussis (DTaP) vaccine containing pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) or one of two commercially available whole-cell pertussis (DTP) vaccines at 2, 4 and 6 months. One month after the third immunization, IgG antibody values to pertussis toxoid, filamentous hemagglutinin and PRN were significantly greater following DTaP than either DTP (P<0.05). When reactions within 48 h after all three doses of vaccine were combined, fever 101°, ≥moderate fussiness, ≥moderate pain, swelling 10 mm, and erythema 10 mm occurred less often after DTaP compared with DTP-Connaught (P<0.001). The same adverse events were also less after DTaP compared with DTP-Lederle (P<0.05), except for erythema 10 mm. This three-component DTaP vaccine produced fewer adverse events and greater antibody values to PT, FHA and PRN in comparison with either licensed DTP vaccine when given as the primary series.; Acellular pertussis vaccine; whole-cell pertussis vaccine; immunization
We used an immunoblotting technique to compare the serum antibody responses to pertussis toxin (PT), filamentous hemagglutinin
(FHA), a 69-kilodalton (kDa) adenylate cyclase-associated protein (69 KD protein), and Bordetella pertussis outer membrane proteins (OMPs) following either B. pertussis infection or immunization with whole-cell pertussis vaccine. Infection and vaccination induced nearly equally intense antibody
responses to PT and to FHA, but vaccination induced stronger antibody responses to the 69 KD protein and to many OMPs. The
importance of serum antibody responses to the 69KD protein and to B. pertussis OMPs other than PT and FHA in conferring immunity to pertussis after vaccination is unknown. Serum antibody responses to
PT following either infection or vaccination were almost exclusively to the 28-kDa enzymatic subunit (Sl) and only rarely
and weakly to the lesser molecular weight binding subunits (S2–S5).
PIP
Pertussis is a common, highly infectious, respiratory disease that predominantly affects children. As many as 60 million cases with more than a 1/2 million deaths occur annually. The highest incidence rates are observed in developing countries where immunization coverage is low. Accurate diagnosis under field conditions is hampered by current laboratory methods. The control of pertussis is accomplished largely through immunization and improvement of socioeconomic conditions. Although the adsorbed DPT vaccine is associated with some side effects, its benefits outweigh the risks when the vaccine sequelae are compared with the morbidity and mortality caused by the natural disease. Surveillance of pertussis and outbreak investigations provide valuable information about the disease and its effectiveness of ongoing immunization programs. (author's)
Immunization against pertussis was introduced in Sweden in the 1950s and discontinued in 1979. This was followed by a low endemic level of pertussis for 3 years. Thereafter the incidence gradually increased and there were two outbreaks in 1983 and in 1985. In the period 1980 to 1985 pertussis was confirmed by culture or serology in 36,729 patients of which 11% were younger than 12 months of age and 69% were ages 1 to 6 years. An estimate of the total frequency of pertussis in preschool children was made from reports from a sample of the child health centers. The annual incidence rate per 100,000 population ages 0 to 6 years increased from the 700 cases in 1981 to 3200 in 1985. The ratio of total cases to those reported from the laboratories was 3:1 in 1981 and 2:1 in 1985. The cumulative incidence rate by the average age of 4 years was estimated at 16% of the unimmunized cohort born in 1980 compared with 5% of the immunized cohort born in 1978. The seriousness of pertussis was evaluated by studying the 2282 pertussis patients hospitalized from 1981 to the end of 1983. Forty-eight percent were infants younger than 12 months of age. Neurologic complications were noted in 4% and pneumonia in 14% of the hospitalized patients. Eleven children received assisted ventilation. Fatal outcomes were reported in 3 children (0.1%), 2 of whom had severe congenital disabilities.
Protective activities of the filamentous hemagglutinin (FHA) and the lymphocytosis-promoting factor (LPF) of Bordetella pertussis were compared by active and passive protection tests with intracerebral or respiratory challenge in mice. Mice immunized
twice by intraperitoneal injection of 8 µg of FHA or glutaraldehyde-inactivated LPF were protected after aerosol challenge.
One intraperitoneal injection of inactivated LPF also protected mice from intracerebral challenge; the dose protecting 50%
of the mice was 8.5 µg. However, one intraperitoneal injection of 48 µg of FHA or two weekly intraperitoneal injections of
20 µg did not protect mice from death after intracerebral challenge. Injection of affinity-purified antibody to LPF from mouse
hybridomas or from goats gave a dose-dependent protection against aerosol challenge. The smallest dose giving protection was
80–90 µg. Polyclonal or monoclonal antibody to FHA at doses of 1,440 µg or 360 µg, respectively, gave very little protection
from disease after respiratory challenge. These data indicate that active immunization of mice followed by respiratory challenge
with B. pertussis is a useful model to identify protective antigens.
To compare the reactogenicity of a licensed conventional whole-cell (WCL) and 13 acellular pertussis vaccines that differed in the source, manufacture, and quantity of included antigens; all vaccines included diphtheria and tetanus toxoids.
Healthy infants were enrolled through six university-based vaccine and treatment evaluation units and were randomized to receive one of the study vaccines at 2, 4, and 6 months of age. Parents recorded the occurrence of fever, redness, swelling, pain, fussiness, drowsiness, anorexia, and use of antipyretics for 2 weeks after each inoculation; nurses interviewed parents on the third day and at each succeeding visit; long-term follow-up information was collected from parents and medical records 1 year after the third immunization.
Of 2200 vaccinated infants, 2189 contributed reaction data after 6375 vaccinations. For every acellular vaccine, every monitored reaction except vomiting occurred at a significantly lower frequency and severity than was seen with WCL. The groups receiving acellular pertussis vaccines differed significantly with respect to redness, swelling, pain, and vomiting, but not with respect to fussiness, antipyretic use, drowsiness, or anorexia.
Although there were differences among the acellular vaccines, none was consistently the most or least reactogenic; all were associated with substantially fewer and less severe adverse reactions than a standard commercial whole-cell vaccine. Selection of acellular vaccines for further development and for introduction into efficacy trials can give priority to assessments of immunogenicity and purity, with comparative reactogenicity a secondary consideration.
An acellular pertussis vaccine (DTaP) containing pertussis toxoid, filamentous hemagglutinin and the 69-kDa outer membrane protein (pertactin) was compared with United States-licensed whole cell pertussis vaccine (DTwP) as a three dose sequence at 2, 4 and 6 months of age. Eighty infants were enrolled; 62 received DTaP and 18 received DTwP. Sixty-two infants had preimmunization and 1 month postimmunization sera available for pertussis antibodies. No infant experienced a serious adverse reaction. Significantly fewer infants in the DTaP group experienced irritability (P < 0.001) and moderate to severe injection site pain and redness (P < 0.001, and P = 0.03, respectively). The DTaP group also had significantly greater increases in geometric mean titers of antibodies against filamentous hemagglutinin (P < 0.001) and pertactin (P = 0.006). This three-component DTaP vaccine induced an antibody response to pertussis toxin, filamentous hemagglutinin and pertactin but caused fewer adverse reactions than DTwP when administered as a primary series of immunization to 2-month-old infants.
To evaluate the efficacy of a three-dose primary vaccination with a diphtheria-tetanus tricomponent acellular pertussis vaccine against "typical" pertussis, defined as a spasmodic cough of 21 days or longer with confirmation of Bordetella pertussis infection by culture or serology.
Passive monitoring for suspected first household (index) cases of typical pertussis in six areas in Germany comprising 22,505 children vaccinated with study vaccine at 3, 4, and 5 months of age. Blinded, prospective follow-up of household contacts of index cases for incidence and progression of pertussis.
Six areas in Germany with a high incidence of pertussis.
Four hundred fifty-three households with index cases comprising 360 evaluable contacts eligible for analysis of vaccine efficacy.
Vaccine efficacy from attack rates of pertussis in household contacts classified by vaccination status.
Of the 173 nonvaccinated household contacts, 96 developed typical pertussis, compared with seven of 112 contacts vaccinated with acellular pertussis vaccine. Vaccine efficacy was consequently calculated to be 88.7% (95% confidence interval, 76.6% to 94.6%). Protection did not wane until at least the time recommended for booster vaccination. None of the analyzed potential confounding factors--age, socioeconomic status, erythromycin treatment, household composition, center effect, and selection bias--influenced study results in favor of the vaccine.
Under conditions of intense household exposure, primary vaccination with acellular vaccine protected against pertussis until at least the time recommended for booster vaccination. The vaccine can be expected to be equally or more effective in settings with lower infectious pressure.
To determine the impact of the introduction of acellular pertussis vaccine for the fourth and fifth doses of the diphtheria and tetanus toxoids and pertussis vaccine series in children on rates of reported vaccine-associated adverse events in the United States.
Analysis of postmarketing vaccine adverse event data from the Vaccine Adverse Event Reporting System during the years 1991 to 1993.
Approximately 27 million doses of diphtheria and tetanus toxoids and pertussis vaccine and 5 million doses of diphtheria and tetanus toxoids and acellular pertussis vaccine were distributed from 1991 to 1993 to children 15 months to 7 years of age.
Rates of reported fever, seizures, and hospitalizations after pertussis vaccination.
Rates of reported adverse events per 100,000 vaccinations were significantly lower after administration of diphtheria and tetanus toxoids and acellular pertussis vaccine than diphtheria and tetanus toxoids and pertussis vaccine for the following outcomes: all reports, 2.9 vs 9.8; fever, 1.9 vs 7.5; seizures, 0.5 vs 1.7; and hospitalizations, 0.2 vs 0.9.
These results confirm that minor adverse events are less frequent after administration of the acellular pertussis vaccine. In addition, these data suggested that seizures and hospitalizations associated with pertussis vaccination are less frequent after administration of the acellular pertussis vaccine in age groups for which it is now recommended.
SB-3 (Infanrix-DTPa) is one of a new generation of vaccines for immunisation against pertussis (whooping cough), diphtheria and tetanus. It is a 3-component (pertussis toxin, filamentous haemagglutinin and pertactin) chemically inactivated acellular pertussis pertussis-diphtheria-tetanus toxoid (DTaP) vaccine, and it differs from conventional whole-cell pertussis-diphtheria-tetanus toxoid (DTwP) vaccines in that it comprises inactivated purified Bordetella pertussis antigens rather than whole cells of the bacillus. SB-3, like a number of other DTaP vaccines, elicits a similar or more often, a significantly greater immune response than various DTwP vaccines in healthy infants and young children. initial data from comparative studies indicate that SB-3 also remains immunogenic when given in combination with hepatitis B vaccine or concurrently administered with Haemophilus influenzae type b (HbOC) conjugate vaccine. A combination of SB-3 and H. influenzae type b tetanus (PRP-T) conjugate vaccine results in lower anti-PRP antibody response than when both vaccines are administered concurrently. Data from two large, multicentre, German and Italian studies in infants indicate that the protective efficacy of SB-3 against pertussis was significantly better than one DTwP (DTwP-CON) but similar to another one (DTwP-BW) under investigation. Compared with another DTaP vaccine (BIO-3), SB-3 was just as protective. Overall, the data from these 2 studies indicate that primary vaccination with SB-3 provides effective protection against pertussis, even under the stringent conditions of a household contact with typical pertussis. As the other DTaP vaccines, SB-3 is better tolerated than DTwP vaccines, with a significantly lower incidence of common adverse events such as local reactions (swelling, pain and a erythema), irritability, fever, persistent crying and local tenderness. Clinical experience with SB-3 thus far indicates that, like other DTaP vaccines, it is associated with significantly fewer common (non-serious) adverse events than DTwP vaccines. Less clear is whether it has any advantage over DTwP vaccines with respect to protective efficacy or over other DTaP vaccines with respect to tolerability and protective efficacy. Nevertheless, the available data support the use of SB-3 for infant immunisation, as well as providing a suitable basis for the development of new combination vaccines.
To assess the safety and tolerability of 12 lots of SmithKline Beecham Biologicals' diphtheria-tetanus-tricomponent acellular pertussis vaccine (DTaP) in a large cohort of 22,000 vaccinees, with detailed analyses of reactivity, immunogenicity, and immune response to pertussis toxin in subsets.
In a prospective, double-blind, multicenter trial in Germany, 22,505 healthy infants received three vaccinations of DTaP at age 3, 4, and 5 months. Serious adverse events were followed for 1 month after each vaccination, and neurologic events for 1 year or longer. Serum IgG antibodies were assayed before vaccination and 1 month after vaccination.
After 67,000 doses, 153 serious adverse events (0.23%) were reported, 8 considered possibly related, and 5 related to vaccination, including 1 hypotonic-hyporesponsive episode. Incidence rates of sudden infant death syndrome (7; 0.01%) or acute neurologic events (20; 0.030%) were no higher than expected and not considered to be related to vaccination. Redness and swelling of 20 mm or greater occurred after 44 (0.6%) and 40 (0.6%) of the 7270 doses, respectively, and high fever (> 39.5 degrees C) in 6 (0.08%) subjects within 48 hours of vaccination. In the immunogenicity analysis of 580 infants, 98% responded to pertussis toxin, 96% to filamentous hemagglutinin, and 98% to pertactin. In an additional 5712 infants, the response rate to pertussis toxin was 99%.
In a large cohort of 22,505 infants vaccinated, SmithKline Beecham Biologicals' tricomponent DTaP vaccine was shown to be safe, well-tolerated, and immunogenic for all component antigens.
To evaluate the persistence of specific antibodies induced by primary immunization with three doses of two three-component acellular vaccines against pertussis with an observed efficacy of 84%, and one whole-cell vaccine with an observed efficacy of 36%.
Serum samples were collected from a subsample of 1572 children from the Italian double-blind, placebo-controlled, randomized trial of vaccines used in 15,601 children at three time points: before administration of the first dose of vaccine, and 1 month and approximately 15 months after administration of the third dose. Further evaluation included pooled cross-sectional analysis of serum specimens associated with episodes of cough (which were not laboratory confirmed as pertussis infection) occurring among the entire population enrolled in the trial.
With both acellular vaccines there was a fast and steep decrease in geometric mean antibody titers to pertussis toxin, filamentous hemagglutinin, and pertactin after vaccination. Mean titers were close to the limit of detection 15 months after primary immunization. The immunogenicity of the whole-cell study vaccine was poor 1 month after the third dose, and no antibody was detected in nearly all children 15 months after whole-cell vaccination.
Although the study acellular pertussis vaccines induced a strong primary specific antibody response in almost all recipients, the duration of the response was limited. Sustained high-level production of antibody to the antigens tested does not account for the observed efficacy of acellular pertussis vaccines.
Pertussis vaccines: WHO position paper
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WHO Wkly Epidemiol Rec 1999; 74: 137-42.
Evaluation of the Childhood Immunisation Programme in Singapore
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Anonymous. Evaluation of the Childhood Immunisation
Programme in Singapore. Communicable Disease
Surveillance in Singapore, 1997: 8-11.
Purification, characterization and immunological evaluation of the 69-Kda outer membrane protein of Bordetella pertussis
- C Capiau
- S A Carr
- M E Hemling
Capiau C, Carr SA, Hemling ME, et al. Purification,
characterization and immunological evaluation of
the 69-Kda outer membrane protein of Bordetella
pertussis. In: Manclark CR, ed. Abstracts of Sixth
International Symposium on Pertussis. Bethesda,
MD: Department of Health and Human Services;
Reactogenicity and immunogenicity of a three -component acellular pertussis DTPa vaccine compared to the conventional whole-cell DTPw vaccine
- S Wiersbitzky
- H L Bock
- R Bruns
Wiersbitzky S, Bock HL, Bruns R, et al. Reactogenicity
and immunogenicity of a three -component acellular pertussis DTPa vaccine compared to the conventional whole-cell DTPw vaccine. Monatsschr
Kinderheilkd 1996; 144: 159-66.
Overview of the clinical development of a diphtheria-tetanus-acellular pertussis vaccine
- H Bogaerts
- C Capiau
- P Hanrer
Bogaerts H, Capiau C, Hanrer P, et al. Overview of the
clinical development of a diphtheria-tetanus-acellular pertussis vaccine. J Infect 1996; 174 (suppl 3):
S276-S280.