Luis Barreto

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.

Declining pertussis incidence in Sweden following the introduction of acellular pertussis vaccine

Acellular pertussis vaccines were introduced nation-wide in Sweden in 1996, 17 years after the withdrawal of whole-cell pertussis vaccine from the childhood immunisation schedule. We report national data on age specific incidence of culture-confirmed Bordetella pertussis for 1986-2000, and clinical follow-up for 3 years (October 1997-September 2000) in children born in 1996-2000 and from children born in 1993-1994 who had participated in a trial of pertussis vaccines. The annual incidence of culture-confirmed B. pertussis was 89-150 per 100,000 before introduction of acellular pertussis vaccines and has dropped to 17-26 per 100,000. The data suggest that unimmunised infants and children who have received only one dose of pertussis vaccine were provided some protection. The decline is most obvious from the second dose onwards and remained stable for 4-5 years after the third dose in the absence of any booster dose. The first signs of waning immunity were observed at 6-7 years of age in the trial cohort. The short-term benefits reflect high vaccination coverage and high initial efficacy. The full impact of the acellular pertussis vaccination programme in infants remains to be established.

Inactivated poliovirus vaccine : Past and present experience

Many countries have made use of inactivated poliovirus vaccine (IPV) in their national poliovirus control programs since 1955. Until 1961 IPV was the only vaccine available for the control of poliovirus, but subsequently many countries opted to use the Sabin attenuated poliovirus vaccine (OPV), which was perceived as more effective in preventing intestinal infection and in ensuring community protection by spreading to unvaccinated contacts of vaccinees. Nevertheless, IPV has remained the vaccine of choice in several countries, where experience has shown that it represents a safe and effective option for disease control. IPV limits subsequent infection of the pharynx and intestine in vaccinees, and is able to control circulation of poliovirus in a vaccinated population, providing effective community protection. Furthermore IPV contains only killed virus and cannot cause vaccine-associated paralytic poliomyelitis as OPV sometimes does. This paper reviews the history of the use of IPV, with emphasis on its efficacy and its ability to safely protect communities in which it is used. As the incidence of poliomyelitis declines new control strategies should take account of the knowledge of the use of poliovirus vaccines acquired since 1955.

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.

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.

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 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.

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.

Predicted long-term persistence of pertussis antibodies in adolescents after an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine, based on mathematical modeling and 5-year observed data.

In a clinical trial, adolescents who had received a booster dose of reduced dose diphtheria-tetanus-5-component acellular pertussis vaccine (Adacel, Tdap) 5 years earlier maintained increased antibody concentrations to all antigens compared with pre-vaccination values. Observed data were applied to several mathematical models designed to predict further antibody decay for pertussis antigens. A linear mixed model including a random-intercept term provided the best fit for the observed data and was used for predictions. The predicted times for sufficient antibody decay to reach pre-vaccination levels were 15.3 years (95% CI: 7.0-28.0) for pertactin, 11.0 years (5.7-18.9) for fimbriae types 2 and 3, 10.5 years (3.6-24.7) for pertussis toxoid and 9.5 years (4.2-24.6) for filamentous hemagglutinin. For at least 87% of subjects, the 10-year predicted antibody concentration was higher than the limit of quantitation (LOQ) for each pertussis antigen measured. These results support Tdap booster doses every 10 years, following the current schedule for Td vaccination.

Nature, evolution, and appraisal of adverse events and antibody response associated with the fifth consecutive dose of a five-component acellular pertussis-based combination vaccine

We performed a randomized, controlled clinical trial to characterize the evolution of the adverse events associated with the fifth consecutive dose of an acellular pertussis vaccine, and to assess the level of discomfort associated with the injection and the attitude of parents concerning these events. A total of 505 children who had received either four doses of acellular pertussis vaccine or whole-cell pertussis vaccine were given a fifth dose of one of the two vaccines. Adverse events were monitored by parents and collected by telephone or home visit at 4, 8, 12, 24, 48 and 72 h, and 7 and 28 days after immunization. Rates of injection site redness >or=50mm were similar in recipients of five doses of acellular pertussis vaccine (32.8%) or five doses of whole-cell pertussis vaccine (43.3%). Injection site swelling, tenderness, and decreased arm movement were all more frequent in children who received five doses of whole-cell pertussis vaccine. Antibody levels before or after immunization did not predict those children who had increased injection site reactions. The children rated the injection site reactions as significantly more severe after five consecutive doses of whole-cell vaccine. Parent satisfaction was higher after the acellular vaccine. We conclude that a fifth consecutive dose of a whole-cell pertussis vaccine is associated with high rates of tender redness and swelling at the injection site, in contrast to a fifth consecutive dose of an acellular pertussis vaccine which is associated with high rates of non-painful redness. However, parents will still need to be aware of the high rates of injection site reactions expected after a fifth dose of acellular pertussis vaccine.