Humoral immunity 10 years after booster immunization with an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine.

Persistence of antibodies after a single dose of Tdap vaccine (tetanus, diphtheria, and 5-component acellular pertussis vaccine) was evaluated in a follow-up study of adolescents (N=324) and adults (N=644) who had received Tdap in earlier clinical trials. Outcome measures were seroprotection (tetanus and diphtheria) or seropositivity (pertussis) and geometric mean concentrations. Humoral immune responses to all antigens were robust 1 month after initial immunization, decreased at subsequent measurements, but continued to exceed pre-immunization levels 1, 3, 5, and 10 years later. Protective levels of diphtheria and tetanus antitoxin persisted in 99.3% of adolescents 10 years after a booster dose of Tdap. Seropositivity to 1 or more pertussis antigens also persisted in most adolescents for 10 years. Although tetanus antitoxin responses were similar in adults to those observed in adolescents, diphtheria antitoxin titers were lower, reflecting the fact that a smaller proportion of adults had received diphtheria toxoid in the previous 10 years compared to adolescents. These data will contribute to the selection of the optimal interval for repeat doses of Tdap.

Humoral immunity 5 years after booster immunization with an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine.

Persistence of antibodies following a single dose of Tdap vaccine (tetanus, diphtheria, and five-component acellular pertussis vaccine for use in individuals past childhood) was evaluated in a follow-up of adolescents (N=324) and adults (N=644) who had received Tdap in earlier clinical trials. Outcome measures were seroprotection (tetanus and diphtheria) or seropositivity (pertussis) and geometric mean titers. Humoral immune responses to all antigens were robust 1 month after initial immunization; antibodies exceeded pre-immunization levels 1, 3, and 5 years later. These data will contribute to selecting the optimal interval for booster doses of Tdap.

Safety and immunogenicity of a pentavalent combination vaccine (diphtheria, tetanus, acellular pertussis, polio, and haemophilus influenzae type B conjugate) when administered as a fourth dose at 15 to 18 months of age.

A DTaP-IPV//PRP-T combination vaccine (Pentacel) has been universally used in Canada to provide immunization against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b with single injections at 2, 4, 6 and 18 months of age. This randomized, multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age, similar to the US immunization schedule. Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and randomized to receive a fourth dose at 15, 16, 17 or 18 months. Antibody levels for each vaccine antigen were measured prior to and four weeks following booster vaccination. Overall, 1782 subjects were immunized and monitored for adverse events, and 735 were evaluated for immune responses. Preimmunization antibody levels differed minimally by age, for all antigens. The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months, as demonstrated by specific antibody geometric mean titers, seroprotection/seroresponse rates, and reverse cumulative distribution curves. The fourth dose was well tolerated in all age groups. Toddlers at 15, 16, 17 or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine.

Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults.

BACKGROUND: Pertussis is increasingly recognized as an important cause of cough illness in adolescents and adults. PURPOSE: To evaluate the safety and antibody response to a single dose of an adult formulation of a five component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine (aP) combined with diphtheria and tetanus toxoids (TdaP) and inactivated poliovirus vaccine (TdaP-IPV) in adolescents and adults and to assess the response to a second dose of the acellular pertussis vaccine in a subset of the adults. POPULATION AND SETTING: The study addressed 1207 healthy participants (736 adults and 466 adolescents) recruited in five Canadian communities. STUDY DESIGN: In a randomized, observer-blind, controlled clinical trial, adult participants received Td followed at a separate visit by aP, TdaP followed by IPV or TdaP-IPV; adolescents received Td-IPV followed at a separate visit by aP or TdaP-IPV. A subgroup of adults was given a booster of aP 1 month after TdaP. OUTCOME MEASURES: Antibody titers measured before and 1 month after each immunization; adverse events enumerated at 24 h, 72 h and 8 to 10 days. RESULTS: The aP vaccine given by itself was associated with adverse events less frequently than were Td, Td-IPV, TdaP or TdaP-IPV vaccines, but reaction rates did not differ significantly among the latter products. The antibody response against Bordetella pertussis antigens was vigorous in all groups, although adults given the TdaP-IPV vaccine had lower antibody titers against filamentous hemagglutinin, pertactin, diphtheria and tetanus antibodies than those given TdaP vaccine. Similarly adolescents given TdaP-IPV had lower antibody titers against pertussis toxin, filamentous hemagglutinin, fimbriae and agglutinins than those given Td-IPV and aP alone. A second dose of acellular pertussis vaccine was not associated with increased adverse events in adults but elicited increased antibody titers over that achieved by a single dose only against pertussis toxin. CONCLUSIONS: This adult formulation five component aP vaccine given as TdaP-IPV is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.

An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults.

Pertussis is increasingly being recognized as an important cause of cough illness in adolescents and adults. To evaluate the safety and immunogenicity of an adult formulation of a five-component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine combined with diphtheria and tetanus toxoids, we randomly allocated 749 healthy adolescents and adults from 12-54 years of age recruited from five Canadian communities to receive either tetanus-diphtheria vaccine (Td), acellular pertussis vaccine (aP) or combined diphtheria-tetanus-acellular pertussis vaccine (TdaP). Subjects and personnel were unaware of the vaccine allocation. Antibody levels were measured before and one month postimmunization; adverse events were collected at 24 and 72 h and 8 to 10 days. Adverse events were reported in similar frequency amongst the three vaccine groups. Moderate pain at the injection site was reported less frequently in the aP group than the TdaP group (10.7% compared to 19.4%; relative risk 0.6, 95% confidence interval 0.3-0.9). Chills were reported less frequently after Td (5.3%) than after TdaP (12.5%; relative risk 0.4, 95% confidence interval 0.2-0.9). There were no statistically significant differences between recipients of Td and TdaP in tetanus and diphtheria antitoxin levels achieved. Antibody response against Bordetella pertussis antigens was vigorous in all groups although recipients of aP alone had higher levels of antibody levels against pertussis toxoid, fimbriae, and agglutinins and lower antibody levels against pertactin than did TdaP recipients. We conclude that this adult formulation 5-component acellular pertussis vaccine is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.

Comparison of a fifth dose of a five-component acellular or a whole cell pertussis vaccine in children four to six years of age.

BACKGROUND AND OBJECTIVES: Acellular pertussis vaccines are now preferred for all five childhood immunization doses; however, there are few data on the safety and immunogenicity of five consecutive doses. This study compared a fifth dose of an acellular and a whole cell pertussis vaccine in 4- to 6-year-old children previously immunized with four doses of acellular or whole cell pertussis vaccine. STUDY DESIGN: In a double blind, multicenter study, 366 healthy children were randomly allocated to receive a single injection of a 5-component acellular or a whole cell pertussis vaccine, each combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine. RESULTS: Although injection site redness > or =50 mm and swelling > or =50 mm were common in children who had received five doses of acellular (50% and 48.1%, respectively) or whole cell (66.2% and 59.7%) pertussis vaccine, limb soreness and limitation of motion were less frequently reported after acellular (1.9% and 0%) than after whole cell (49.2% and 36.3%; P < 0.0001) pertussis vaccine. Pre-fifth dose antipertussis antibody titers were higher in children who previously had received four doses of acellular pertussis vaccine. Postimmunization antibody titers against pertussis toxin, filamentous hemagglutinin, pertactin and tetanus toxin were higher in recipients of five doses of acellular pertussis vaccine, whereas antibody titers to diphtheria toxin, pertussis fimbriae and poliovirus serotypes were higher in recipients of five doses of the whole cell pertussis vaccine (P < 0.05 for all comparisons). CONCLUSIONS: A regimen consisting of five doses of a five-component acellular pertussis combination vaccine is safe and immunogenic in pre-school children. Local adverse reactions are common but are less painful and activity-limiting than a regimen of five doses of a whole cell pertussis vaccine.

Extended follow-up of antibody levels and antigen responsiveness after 2 Haemophilus influenzae type b conjugate vaccines.

Although immunization programs with Haemophilus influenzae type b (Hib) conjugate vaccines have dramatically reduced disease incidence, few data are available regarding the duration of protection after vaccination. We measured serum anti-polyribosylribitol phosphate (PRP) levels in healthy 4- to 5- year-old children previously given 4 doses of PRP-T vaccine (at 2, 4, 6, and 18 months) or 1 dose of PRP-D vaccine (at 19 months) during clinical trials to assess antibody persistence. Concurrent with other preschool immunizations, half of the children were randomly assigned to receive a PRP-T booster immunization to assess responsiveness. Among 136 subjects who were primed with PRP-D, the baseline geometric mean concentration of antibody was 0.7 microg/mL (95% CI 0.5 to 0.9). Concentrations were <0.15 microg/mL in 24 (17.6%) subjects. Among 212 children who were primed with PRP-T, the geometric mean concentration was 2.2 microg/mL (95% CI 1.9 to 2.5) (P <.001). Only 2 (0.9%) had concentrations <0.15 microg/mL. Four weeks after PRP-T immunization, geometric mean concentrations had increased to 98.4 and 102.0 microg/mL, respectively. Responses were strong even in those with low or undetectable preimmunization antibody levels. Spontaneous increases in antibody levels were seen in 9 (5.2%) of 172 subjects not given additional PRP-T. We concluded that among 4- to 5-year-olds, anti-PRP levels remained above 0.15 microg/mL in nearly all children after PRP-T priming and in most after PRP-D priming, and that both groups were able to respond vigorously to restimulation, consistent with persistent immune memory.

Safety and immunogenicity of a combined five-component pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus B conjugate vaccine administered to infants at two, four and six months of age.

Safety, immunogenicity and lot consistency of five-component pertussis combination vaccine (CPDT-IPV//PRP-T) in infants were compared to that of whole cell pertussis combination vaccine (DPT-IPV//PRP-T), as were separate and combined injections of CPDT-IPV and PRP-T. No significant differences in adverse event rates were observed between lots of CPDT-IPV//PRP-T or between separate or combined injections of CPDT-IPV and PRP-T. Minor differences in antibody responses were observed between lots of component pertussis vaccine. Higher concentrations of diphtheria and tetanus antitoxins were induced by separate than by combined injection of CPDT-IPV and PRP-T, but no other differences in immunogenicity were observed. Adverse reactions were more than twice as frequent after whole cell than after component pertussis vaccines. Antibody responses to pertussis toxoid, filamentous hemagglutin and pertactin were significantly greater after component vaccines, while the response to type 3 poliovirus was higher after whole cell vaccine. No significant differences were observed for other vaccine components. CPDT-IPV//PRP-T was safe and immunogenic in infants. Antibody results were similar to those observed in a Swedish field trial that demonstrated CPDT to be 85% effective in preventing clinical pertussis.

Safety and immunogenicity of two inactivated poliovirus vaccines in combination with an acellular pertussis vaccine and diphtheria and tetanus toxoids in seventeen- to nineteen-month-old infants.

OBJECTIVES: To compare the safety and immunity of an acellular pertussis vaccine containing pertussis toxoid, filamentous hemagglutinin, 69 kd protein, fimbriae 2 and 3 combined with diphtheria and tetanus toxoids given as single or separate injection with inactivated poliovirus vaccine (MRC-5-or Vero cell-derived) or live attenuated polio vaccine. METHODS: A total of 425 healthy children between 17 and 19 months of age who were receiving the fourth dose of their routine immunization series were randomly allocated to receive either the acellular pertussis vaccine and oral poliovirus vaccine or one of two inactivated poliovirus vaccines as a combined injection or separate injections. RESULTS: Although minor adverse events were commonly reported, differences between the groups were few. Fever and decreased feeding were less common in recipients of live attenuated poliovirus vaccine than the combination vaccine containing MRC-5 cell-derived inactivated poliovirus vaccine. A significant antibody response was demonstrated in all groups against all the antigens contained in the vaccines. Antibodies against poliovirus were higher in the groups immunized with the inactivated poliovirus vaccine than the live attenuated vaccine. Anti-69 kd protein antibodies were higher in the group given the MRC-5 cell-derived inactivated poliovirus vaccine as a combined injection than in the group given the separate injection or the group immunized with the live attenuated poliovirus vaccine. CONCLUSION: The five-component acellular pertussis vaccine combined with diphtherid and tetanus toxoids is safe and immunogenic when combined with either MRC-5- or Vero cell-derived inactivated poliovirus vaccine. This will facilitate the implementation of acellular pertussis vaccine and the movement to inactivated poliovirus vaccine programs.

Adverse reactions and antibody response to four doses of acellular or whole cell pertussis vaccine combined with diphtheria and tetanus toxoids in the first 19 months of life.

To assess the safety, immunogenicity, and lot consistency of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoid (Connaught Laboratories Limited), we randomly allocated 432 infants to receive one of three lots of an acellular pertussis vaccine or a single lot of whole cell pertussis vaccine. Infants were immunized at 2, 4 and 6 months of age and between 17 and 19 months of age. Local and systemic adverse reactions were reported significantly more frequently by recipients of the whole cell than acellular vaccine after each dose. The antibody response against pertussis toxin, filamentous hemagglutinin, and 69 kDa protein was of greater magnitude in acellular pertussis vaccine recipients than whole cell pertussis vaccine recipients. Small differences were detected amongst the vaccine lots tested. We conclude that the acellular pertussis vaccine is safe and immunogenic for the first four doses in children under 2 years of age.

Evaluation of booster doses of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in 18-month-old children.

A booster dose of Haemophilus influenzae type b conjugate vaccine in the second year of life is the final step in the recommended series of doses to protect infants from invasive infection. This study assessed the safety and immunogenicity of PRP-T conjugate vaccine booster doses (Act-HIB, Connaught Laboratories Ltd). The participants were 367 healthy children who had taken part in a study of primary immunization with PRP-T. At 18-19 months old, subjects were randomly assigned to receive diphtheria-pertussis-tetanus (DPT) and PRP-T vaccines either mixed in one syringe (n = 183) or separately in opposite limbs (n = 184). Adverse events were monitored for 48 h after immunization. Blood was obtained prior to vaccination in half of the subjects (combined injections group) and following vaccination in all subjects to test for antibodies to each of the antigens administered. Local adverse reactions were infrequent with PRP-T alone and equally frequent at sites of DPT or DPT/PRP-T injection, except for redness > or = 25 mm in diameter which was more frequent after the combined vaccines (25.1 versus 14.1%, p < 0.01). Systemic adverse events did not differ in type or frequency between groups. Before immunization, the geometric mean anti-PRP level in those tested was 0.41 micrograms ml-1; 26.7% had levels below 0.15 micrograms ml-1. Both treatment groups responded strongly to vaccination. In those serially tested, anti-PRP levels rose by over 90-fold, to 38.1 micrograms ml-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate) administered concurrently or combined with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine to healthy infants at two, four and six months of age.

The safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate (PRP-T) administered concurrently in separate sites or mixed in the same syringe with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine were assessed in 439 infants at 2, 4 and 6 months of age. The proportions with local redness, tenderness and swelling in the separate and combined groups were 18% vs. 11% (P < 0.001), 27% vs. 24% and 15% vs. 13%, respectively. Systemic reactions occurred at similar rates in both groups. The combined vaccine induced tetanus and diphtheria antitoxin titers > or = 0.01 IU/ml in 99.5 and 99.1% of infants, pertussis agglutinin titers > or = 64 in 92.4%, anti-polyribosylribitol phosphate titers > or = 0.15 microgram/ml in 93.8% and > or = 1.0 microgram/ml in 75% and polio-neutralizing titers > or = 8 in > 98% of infants. However, antibody concentrations to PRP-T, some pertussis antigens and tetanus toxoid were significantly lower after combined than after separate injections of DPT/diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine and PRP-T. The clinical significance of these differences is not known, but the interactions observed among the components of the pentavalent vaccine may be of concern because they might influence antibody persistence until the fourth dose is administered.

Immunogenicity of a five-component acellular pertussis vaccine in infants and young children.

OBJECTIVE: To compare the reactogenicity and immunogenicity of an acellular vaccine containing pertussis toxoid, filamentous hemagglutinin, and fimbriae 2 and 3, with and without the 69-kd membrane protein, alone or combined with diphtheria and tetanus toxoids. PARTICIPANTS AND SETTING: One hundred thirty-seven 17- to 18-month-old and 22 4- to 6-year-old children who had received three or four previous doses of whole-cell vaccine, respectively, were recruited from public health immunization clinics. DESIGN AND INTERVENTIONS: Three groups of children were sequentially enrolled in the study to receive the acellular pertussis vaccine with or without a 69-kd protein (CP4 or CP5, 17- to 18-month-old children), the two vaccines combined with diphtheria and tetanus toxoids (CP4DT or CP5DT, 17- to 18-month-old children), or the CP5DT vaccine (4- to 6-year-old children). Children were assigned to the first two groups in a randomized and double-blind fashion; the last group was formed by open enrollment. Data regarding adverse reactions were recorded by the parents and collected via a structured interview administered seven times, five times during the first 72 hours. Serum samples were obtained before and 1 month after the immunization, and antibodies against each constituent of the vaccine were measured. RESULTS: A systemic adverse reaction was reported in 40% to 65.7% of 17- to 18-month-old and 38.1% of 4- to 6-year-old children; no severe reactions occurred. A local reaction was reported in 8.6% to 29.4% and 71.4% of children, respectively. No differences were detected between respectively. No differences were detected between vaccines; inclusion of the 69-kd membrane protein did not increase reactogenicity. All vaccines elicited an antibody response to all antigens contained in the formulation. CONCLUSIONS: The five-component acellular pertussis vaccine (Connaught Laboratories Ltd, Willowdale, Ontario) is safe and immunogenic in 17- to 18-month-old and 4- to 6-year-old children. The 69-kd protein was immunogenic, and its inclusion neither increased side effects associated with the vaccine nor adversely affected the antibody response to the other components.

Evaluation of Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) in Canadian infants.

OBJECTIVE: To assess adverse effects and immune responses with a three-dose series of Haemophilus influenzae type b meningococcal protein conjugate (PedvaxHIB or Hib.OMP) vaccine, including any immunological response alterations from concurrent administration with routine vaccines for infants. DESIGN: Randomized, controlled trial with treatment group crossover for dose 3. SETTING: Two public health units near Vancouver. PARTICIPANTS: One hundred and ten healthy infants eight to 14 weeks old were enrolled; 105 completed the study (95%). INTERVENTIONS: All participants received two doses of diphtheria-pertussis-tetanus (dpt) vaccine (at two and four months of age) and one dose of measles-mumps-rubella (mmr) vaccine at 12 months. In each instance, Hib.OMP was given either concurrently in another limb or after a delay of two weeks (after dpt) or four weeks (after mmr). MAIN OUTCOME MEASURES: Adverse effects, particularly fever and local erythema, were monitored by parents for 72 h after each dose of Hib.OMP vaccine. Five blood samples were taken at prescribed intervals to assess responses to each dose of Hib.OMP and to selected other vaccine antigens. MAIN RESULTS: Follow-up was obtained after all 322 doses of Hib.OMP. Local adverse effects were infrequent and mild: 13% had redness, 17% tenderness. Systemic effects in those given Hib.OMP alone included fever in 8%, irritability in 29%. Anti-polyribose-ribitol phosphate (prp) responses to Hib.OMP were not impaired by coadministration with dpt or mmr vaccines, nor were tetanus or diphtheria antitoxin levels or rubella or measles response rates affected. After two doses of Hib.OMP, 92% were seropositive and 64% had greater than 1.0 µg/mL of anti-prp. After three doses, 100% were seropositive and 82% exceeded 1.0 µg/mL. CONCLUSION: Hib.OMP vaccine was well tolerated, immunogenic and compatible with vaccines routinely given to infants in Canada.

Can Haemophilus influenzae type b-tetanus toxoid conjugate vaccine be combined with diphtheria toxoid-pertussis vaccine-tetanus toxoid?

OBJECTIVE: To assess the side effects and immune responses after three serial doses of PRP-T vaccine (a Haemophilus influenzae type b [Hib]-tetanus toxoid conjugate vaccine) given concurrently or mixed with adsorbed DPT vaccine (diphtheria toxoid-pertussis vaccine-tetanus toxoid). DESIGN: Multicentre randomized controlled trial. SETTING: Four public health units in western Canada. PARTICIPANTS: Healthy infants 8 to 15 weeks old at entry who were able to receive routine primary vaccinations. Of 444 infants enrolled, 433 (98%) completed the study. INTERVENTIONS: All infants received PRP-T and DPT vaccines at 2, 4 and 6 months of age: half received them mixed in one injection and the others as separate, bilateral injections. MAIN OUTCOME MEASURES: Side-effects 24 and 48 hours after each dose and serologic responses to each vaccine component. RESULTS: Follow-up was obtained after all 1312 vaccinations. Fever was infrequent in the two treatment groups. Local adverse effects of the PRP-T vaccine were infrequent and mild (e.g., redness was noted in 5.9% of cases and the area of redness was more than 2.5 cm in diameter in 0.8%). The incidence rate of local effects of the DPT-containing vaccines was the same in the two groups except for tenderness, which was more frequent in the group given the mixed vaccine (26.6% v. 17.9%, p < 0.001). Serologic data were available for 97% of the subjects. After the three doses 98.1% of the subjects had a PRP antibody level of 0.15 micrograms/mL or more, and 87.9% had a level of 1.0 micrograms/mL or more, both levels compatible with protection against Hib. Responses to PRP-T were comparable between the treatment groups as were responses to the diphtheria and tetanus toxoids. Pertussis agglutinin titres were reduced after administration of one of two PRP-T lots mixed with DPT vaccine, but responses to four other pertussis antigens were not impaired. CONCLUSION: PRP-T vaccine is well tolerated and immunogenic. Combined PRP-T and DPT vaccines performed satisfactorily and may be the preferred method of administration.

Controlled trial of Haemophilus influenzae type B diphtheria toxoid conjugate combined with diphtheria, tetanus and pertussis vaccines, in 18-month-old children, including comparison of arm versus thigh injection.

A randomized, controlled comparison was made in 175 healthy 18-month-old children given either diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) and haemophilus b diphtheria toxoid conjugate vaccine (PRP/D) concurrently at separate sites (66 children) or a new vaccine combining these products (109 children). Rates of local or systemic adverse effects postimmunization and antibody responses to each component did not differ significantly between groups. DTP-containing vaccines were better tolerated when given in the thigh than in the arm. The combination DTP-PRP/D vaccine performed satisfactorily at 18 months of age, avoiding the inconvenience of two injections.

Adverse reactions to the preschool (fifth) dose of adsorbed diphtheria-pertussis-tetanus vaccine in Canadian children.

OBJECTIVE: To quantify accurately the rate of adverse reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine and to test the hypothesis that large local reactions are attributable to the diphtheria toxoid. DESIGN: Double-blind randomized controlled trial. SETTING: Suburban community public health unit. PARTICIPANTS: Healthy children 4 to 5 years of age with a history of having received four doses of adsorbed DPT vaccine. INTERVENTIONS: Subjects were given either the standard DPT vaccine (with 25 Lf units of diphtheria toxoid) or a modified DPT vaccine (with 10 Lf units of diphtheria toxoid). They were assessed 24 hours later by a nurse. Serum samples obtained before vaccination were tested for diphtheria and tetanus antitoxin levels by means of neutralization assay and enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of large local reactions (an area of redness or swelling or both of 5 cm or greater) 24 hours after vaccination in the two groups. Relation between serum antitoxin levels before vaccination and the rate of large local reactions in each group. RESULTS: Of the 250 subjects enrolled 124 received the standard vaccine and 126 the modified one. Large local reactions occurred in 71% of the subjects receiving the standard vaccine and 52% of those receiving the modified one (p less than 0.01). In the former group large erythematous reactions occurred significantly more often in those with an elevated prevaccination diphtheria antitoxin level than in those without an elevated level; no relation was found between such reactions and the prevaccination tetanus antitoxin level. Reduced arm movement was evident in 45% of the children in the two groups. Few had systemic adverse reactions. CONCLUSIONS: Large local reactions occur frequently after the preschool administration of the DPT vaccine. These reactions are uncomfortable but not serious. They result in part from the large amount of diphtheria toxoid in the standard DPT vaccine.