Diphtheria antitoxin levels among children primed with a diphtheria and tetanus toxoids and acellular pertussis vaccine lot with a subpotent diphtheria toxoid component

One lot of a nationally distributed diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine was recalled in January 1999 because of a subpotent diphtheria toxoid component. To evaluate vaccine immunogenicity, children who had received the recalled lot for at least 2 of the 3 doses of their primary series were identified. Diphtheria antitoxin (DAT) levels were then prospectively assessed before and after dose 4 of (fully potent) DTaP vaccine. Of the 105 children evaluated, 84% had prevaccination DAT levels <0.10 IU/mL, which is the level generally accepted as protective. DAT levels rose a mean of 92-fold after dose 4; 100% of subjects had DAT levels >or=0.10 IU/mL, and 69% had DAT levels >or=1.0 IU/mL. These results indicate that diphtheria potency testing can identify vaccine that is less immunogenic when administered during the primary series. The booster response to dose 4, although reduced, was sufficient to confer adequate protection in the interval before receipt of the fifth dose of DTaP.     

The diphtheria and pertussis components of diphtheria-tetanus toxoids-pertussis vaccine should be genetically inactivated mutant toxins

Replacement of cellular with acellular pertussis (aP) vaccines has considerably reduced the systemic reactions observed with diphtheria-tetanus toxoids-pertussis vaccine but has not eliminated the extensive swelling (sometimes involving an entire limb) observed after the fifth injection of diphtheria-tetanus toxoids-aP (DTaP) vaccine. This local reaction, which is likely an Arthus hypersensitivity reaction caused by high levels of antibodies reacting with DTaP vaccine, could discourage its use in adults, who serve as the major reservoir of pertussis for infants. That a critical level of antibodies to pertussis toxin is both essential and sufficient to prevent infection with Bordetella pertussis is derived from data from animal and clinical studies, including data showing the similarities between the immunity induced by diphtheria and pertussis toxoids. The genetically inactivated diphtheria and pertussis mutant toxins are more immunogenic and, therefore, induce comparable levels of antitoxin at lower protein levels than do the formalin-treated native toxins. Replacement of the diphtheria and aP components with these improved antigens will reduce the amount of protein in DTaP vaccine and, most likely, the incidence and severity of local reactions in teenagers and adults.     

Attributable risk of DTP (diphtheria and tetanus toxoids and pertussis vaccine) injection in provoking paralytic poliomyelitis during a large outbreak in Oman.

Although injections administered during the incubation period of wild poliovirus infection have been associated with an increased risk of paralytic poliomyelitis, quantitative estimates of the risk have not been established. During a poliomyelitis outbreak investigation in Oman, vaccination records were reviewed for 70 children aged 5-24 months with poliomyelitis and from 692 matched control children. A significantly higher proportion of cases received a DTP (diphtheria and tetanus toxoids and pertussis vaccine) injection within 30 days before paralysis onset than did controls (42.9% vs. 28.3%; odds ratio, 2.4; 95% confidence interval, 1.3-4.2). The proportion of poliomyelitis cases that may have been provoked by DTP injections was 35% for children 5-11 months old. This study confirms that injections are an important cause of provocative poliomyelitis. Although the benefits of DTP vaccination should outweigh the risk of subsequent paralysis, these data stress the importance of avoiding unnecessary injections during outbreaks of wild poliovirus infection.     

Cell-mediated immunity and antibody responses to Bordetella pertussis antigens in children with a history of pertussis infection and in recipients of an acellular pertussis vaccine

Cell-mediated immunity (CMI) and antibody responses to Bordetella pertussis antigens were assessed 4-6 years after primary infant immunization with diphtheria-tetanus tricomponent acellular pertussis (DTaP) or diphtheria-tetanus (DT) vaccine in a country with high endemicity of B. pertussis infection. CMI to the B. pertussis antigens (especially to the pertussis toxin [PT]) was more frequent and/or intense in DTaP than in DT recipients. No lymphoproliferation differences were found between those with and without a history of pertussis although the DT recipients produced very little interferon-gamma after antigen (particularly PT and filamentous hemagglutinin [FHA]) stimulation. In contrast, seropositivity to PT, but not to pertactin or FHA, was more frequent in DT recipients with history of pertussis than in all other subjects. Thus, years after disease or vaccination, CMI response to PT or circulating PT antibodies appears to be the main distinctive feature of pertussis-protected DTaP recipients or pertussis-affected DT recipients.     

Controlled study of a new five-component acellular pertussis vaccine in adults and young children.

A new five-component acellular pertussis (AP) vaccine containing 10 micrograms of pertussis toxoid, 5 micrograms of filamentous hemagglutinin, 5 micrograms of combined agglutinogens 2 and 3, and 3 micrograms of pertactin was evaluated in adults and young children. AP vaccine was compared with saline placebo in 31 adults, and AP vaccine combined with diphtheria and tetanus toxoids (ADTP) was compared with whole cell DTP in 41 children, ages 16-20 months, who had received whole cell DTP during infancy. AP was mildly to moderately reactogenic in adults, with pain noted within 72 h and 5-8 days after immunization. ADTP was less reactogenic than DTP in children, with significantly decreased pain, redness, irritability, and fever and less use of acetaminophen reported. No late reactions were observed in any child. The multicomponent ADTP was immunogenic, with four-fold or greater antibody rises to at least four pertussis antibody assays in all 15 immunized adults. Pertussis-specific antibody responses in children who received ADTP and DTP were similar. The multicomponent ADTP vaccine is currently being studied in a National Institute of Allergy and Infectious Diseases-sponsored efficacy study in Sweden.     

A comparison of pertussis rates in the Northwest Territories: Pre- and postacellular pertussis vaccine introduction in children and adolescents.

INTRODUCTION: During the past decade, a trend toward increasing cases of Bordetella pertussis in older children and adults has been witnessed in Canada. The National Advisory Committee on Immunization now recommends that the adult formulation of the acellular pertussis (adult dTap) vaccine combined with diphtheria and tetanus toxoids be substituted for diphtheria and tetanus toxoids alone for the 14- to 16-year-old booster dose. In October 2000, the government of the Northwest Territories was one of the first to adopt adult dTap into their territorial immunization program free of charge. OBJECTIVE: To evaluate the effect of the acellular pertussis vaccine in children and adolescents on the epidemiology of pertussis in the Northwest Territories. METHODS: Pertussis is a reportable disease in the Northwest Territories, and data on the incidence rates of pertussis are available from 1989 to 2004. The present study reviews pertussis cases during three four-year periods: the whole-cell vaccine era (1993 to 1996); the preadult dTap era (1997 to 2000); and the postadult dTap era (2001 to 2004). RESULTS: The incidence of pertussis decreased from 18.0 cases per 10,000 population in 1993 to 0.2 cases per 10,000 population in 2004. The number of cases decreased from 186 to 129 to 19 cases in the three chronological time periods (ie, whole-cell vaccine era, preadult dTap era and postadult dTap era, respectively), with the most substantial reduction coming with the introduction of postadult dTap. CONCLUSIONS: There appears to be a decrease in the incidence of pertussis with the targeted introduction of adult dTap in the Northwest Territories.     

Seroimmunity to diphtheria and tetanus among mother-infant pairs; the role of maternal immunity on infant immune response to diphtheria-tetanus vaccination

BACKGROUND: This study was designed to determine the levels of immunity against diphtheria and tetanus in 110 mothers with/without diphtheria-tetanus toxoid (dT) vaccination during pregnancy and their two-month-old infants before diphtheria-tetanus-pertussis (DTP) immunisation, and also to assess the influence of pre-vaccination passive immunity on the infants' immune response to three doses of DTP vaccination. SUBJECTS AND METHODS: Sera from 110 mother-infant pairs before DTP vaccination and from 69 infants after receipt of three doses of DTP vaccine were tested to measure antidiphtheria-antitetanus toxin IgG levels, using a commercial enzyme immunoassay. History of dT toxoid vaccination of mothers at pregnancy was recorded. RESULTS: 20% of mothers did not receive dT vaccine. Among these 22 unvaccinated mothers, one (5%) and six (27%) were serologically susceptible to tetanus and diphtheria respectively. The mean concentrations of antibody titers were lower in unvaccinated than in vaccinated mothers: diphtheria 0.78 (0.30) IU/mL vs 0.31 (0.20), and tetanus 1.95 (1.20) IU/mL vs 0.51 (0.45), vaccinated mother vs unvaccinated. All infants (100%) acquired immunity against both infections after receipt of three doses of DTP vaccine. Pre-vaccination passive immunity did not influence the infants' immune response to vaccination: diphtheria 0.95 (0.40) vs 0.89 (0.25), and tetanus 2.30 (1.0) vs 2.30 (0.70), from passive immune infants before vaccination vs those without, respectively. CONCLUSION: This study showed that diphtheria-tetanus toxoid components of DTP vaccine were highly immunogenic and maternal passive immunity did not affect the infants' immune response to DTP vaccination. Since there is a 23% missed opportunity for dT immunisation, efforts must be made to increase the coverage rate of this highly immunogenic vaccine in order to sustain protection against diphtheria and tetanus in mothers and their infants..     

Low seroprevalance of diphtheria,tetanus and pertussis in ambulatory adult patients: the need for lifelong vaccination

BackgroundTetanus, diphtheria, pertussis and measles are vaccine preventable diseases that have been reported to cause morbidity and mortality in adult population in the recent years. We aimed to document the seropositivity rates and vaccination indication for these four vaccine preventable diseases among adult and elderly patients who were seen as outpatients in a university hospital.MethodsBlood samples for tetanus, diphtheria, pertussis and measles antibodies were obtained. Results were evaluated with regards to protection levels and booster vaccine indications according to the cut-off values.ResultsA total of 1367 patients consented for the study and 1303 blood samples were available for analysis at the end of the study. The antibody levels against measles conferred protection in 98% of patients. However, 65% of the patients had no protection for diphtheria, 69% had no protection for tetanus and 90% of the patients had no protection for pertussis. Only 1.3% of the study population had seropositivity against three of the diseases—Tdap booster was indicated in 98.7%. Multivariable logistic regression showed that tetanus protection decreased with increasing age. Having a chronic disease was associated with a lower rate of protective antibodies for pertussis.ConclusionsWe demonstrated very low rates of protection against three of the vaccine preventable diseases of childhood—diphtheria, pertussis and tetanus. Booster vaccinations are required in adult life in accordance with national and international adult vaccination guidelines. The concept of “lifelong vaccination” should be implemented and every encounter with the patient should be regarded as a chance for catch-up.     

Antibody levels for diphtheria, tetanus and pertussis in young adult females immunized with whole cell pertussis-diphtheria-tetanus toxoid vaccine in infancy

Antibody levels for diphtheria, tetanus and pertussis in 84 young adult females were measured. They had been immunized with whole cell pertussis-diphtheria-tetanus toxoid (DTwP) vaccine as a routine immunization in their infancy. Their history of DTwP vaccination were confirmed in their Maternal and Child Health Handbook, which includes their immunization record. Among the 84 cases, 4 cases (4.7%) had been immunized with the first dose of DTwP, 5 cases (6.0%) with the second dose, 23 cases (27.4%) with the third dose and 52 cases (61.9%) with the fourth dose. Of the 84 cases, 89.3% had received DTwP vaccine more than the third dose. In the 15-19 years after the last DTwP vaccination, the antibody positive rate for diphtheria and tetanus (> or = 0.01 IU/ml) were 86.9% and 94.0%, respectively. On the other hand, antibody positive rate for anti-pertussis toxin (anti-PT) and anti-filamentous hemaggulutinin (anti-FHA) (> or = 10 EU/ml) were 35.7% and 55.9%, respectively. The positive rate for pertussis compared with those for diphtheria and tetanus were lower. These findings suggested that DTwP vaccination in infancy does not provide sufficient immunity for young adults against pertussis, but DTwP vaccination provides adequate immunity against diphtheria and tetanus.     

Serum antibodies to diphtheria-tetanus-pertussis vaccine components in Argentine children

Summary The Argentine vaccination schedule against diphtheria, tetanus and pertussis (DTP) recommends three doses of DTP vaccine at 2, 4 and 6 months of age, two boosters at 18 months and 6 years, a booster dose of tetanus vaccine every 10 years and two doses during pregnancy. To evaluate the effect of this schedule, antibodies against pertussis toxin (PT) and filamentous hemagglutinin (FHA) and against tetanus and diphtheria toxoids were determined by ELISA in serum samples from children (1 month to 6 years) who received different doses of DPT vaccine: 0 dose (n=50), 1 dose (n=25), 2 doses (n=25), 3 doses (n=55), first and second booster (n=25); 25 pregnant women and their offspring, and 45 adults. High antibody levels against PT (>140 EU/ml) and FHA (>80 EU/ml) were recorded in mothers and in the newborn. Antibody titers against PT increased with the number of doses given and decreased with time. Full protection against tetanus (titers >0.1 IU/ml) was observed in the group of adults (0.37 IU/ml), in mothers (4.4 IU/ml) and their newborn offspring (5.5 IU/ml), and in children after receiving the second dose of DTP vaccine (1.86 IU/ml). The immune status for diphtheria was far lower, as most of the groups lacked adequate protection. After the third dose of DTP vaccine, only 78% of the children had antibody titers above the protective level (0.1 IU/ml). Since antibody levels considered to provide full protection were only achieved after the first booster dose of DTP vaccine, the primary three-dose schedule seems to be insufficient to confer adequate immunity in all vaccinees. Because of the high proportion of non-protected adults, a booster dose of Td vaccine should be considered for this group.     

An antibody induction method in mice for the potency assays of diphtheria and tetanus components in combined vaccines

Eleven batches of Adsorbed Diphtheria-Tetanus (DT) vaccines and thirteen batches of Adsorbed Diphtheria-Pertussis-Tetanus (DTP) vaccines were tested for the potency of diphtheria and tetanus components by an Antibody Induction Method (AIM) developed in mice. The potency results obtained were found comparable and did not show any statistically significant difference with those obtained by WHO recommended lethal challenge tests for diphtheria in guinea pigs and for tetanus in mice. AIM in mice is more economical as both diphtheria and tetanus components of combined vaccine can be tested in the same experiment and the procedure also eliminates the use of guinea pigs required in the lethal challenge/conventional tests. The data obtained while testing tetanus component by the conventional antibody induction (IP) method in guinea pigs suggests that minimum requirements laid down in i.p. is too low which may be fixed as at least 3 out of 9 guinea pig sera and should contain > or = 4 units of tetanus antitoxin per ml.     

Evaluation of serology and nasopharyngeal cultures for diagnosis of pertussis in a vaccine efficacy trial

Nasopharyngeal cultures and titer rises in paired sera were evaluated in a placebo-controlled pertussis vaccine efficacy trial. IgG ELISA for filamentous hemagglutinin (FHA) identified 30 (88%) of 34 placebo recipients and 33 (89%) of 37 vaccine recipients with culture-verified Bordetella pertussis infections, whereas IgG ELISA for pertussis toxin (PT) showed higher diagnostic sensitivity in the placebo group than in the vaccine groups. The CHO cell assay did not improve sensitivity. Children with Bordetella parapertussis infections had rises of titers of antibody to FHA of the same magnitude as children with B. pertussis infections. Sensitive serologic criteria, based on the intraassay variations, identified 105 additional culture-negative cases with significant titer rises in paired sera. IgG ELISA for FHA and PT and IgA ELISA for FHA were reliable assays, and bacterial isolation rates were lower in vaccine recipients than in placebo recipients with serologically defined pertussis.     

Gastrointestinal reactions and rotavirus vaccination based upon analysis of the Vaccine Adverse Events Reporting System (VAERS) database for 1999. A model for the calculation of the incidence rates and statistical significance of adverse events following immunization

BACKGROUND/AIMS: The purpose of this study was to extend previous publications and examine the Vaccine Adverse Events Reporting System (VAERS) database for the incidence of gastrointestinal reactions reported following tetra-valent rhesus-human reassortant rotavirus vaccine (RRV-TV). METHODOLOGY: The VAERS database was analyzed for adverse reactions reported for the entire year of 1999 following RRV-TV using Microsoft Access. In this study, the incidence rates of adverse reactions reported to VAERS following acellular diphtheria, pertussis and tetanus (DTaP) vaccine, whole-cell DTP vaccine, live polio (OPV) vaccine and pediatric hepatitis B vaccine were used as control vaccine groups. RESULTS: The results of a chi-square analysis showed that rotavirus vaccine was statistically significantly over represented by serious gastrointestinal reactions in comparison to vaccine control groups. CONCLUSIONS: This analysis demonstrated that the VAERS database provides a way to detect whether RRV-TV elevates the risk of adverse reactions compared to control vaccines given to similar age groups when appropriate denominators (number of annual doses given) are employed. Because of its massive size and the availability of numerous vaccine control groups, the VAERS database provides data on adverse reactions following vaccination that is available nowhere else.     

Diphtheria, tetanus, and pertussis immunizations in adults

Although only few cases of diphtheria are reported annually in the United States, substantial numbers of adults have declining levels of protective serum antitoxin. A recent outbreak of diphtheria in Sweden emphasizes the importance of reimmunizing adults in diphtheria toxoid, included as part of routine use of tetanus/diphtheria toxoid. Tetanus is a completely preventable disease. Yet, most of the 60 to 100 annual cases of tetanus occur in older adults with no prior history of immunization. Tetanus immunization should be a routine part of medical care of all adults. Research currently is aimed at improving the efficacy and safety of pertussis vaccine. Future vaccines may be useful in protecting health care workers and other adults who have extensive contact with children against pertussis.     

Longitudinal analysis of antibody response to immunization in paediatric survivors after allogeneic haematopoietic stem cell transplantation

The long-term antibody responses to re-immunization in recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) have not been well studied. We prospectively and longitudinally evaluated the antibody responses to eight vaccine antigens (diphtheria, tetanus, pertussis, measles, mumps, rubella, hepatitis B, and poliovirus) and assessed the factors associated with negative titres in 210 allo-HSCT recipients at St. Jude Children's Research Hospital. Antibody responses lasting for more than 5 years after immunization were observed in most patients for tetanus (95.7%), rubella (92.3%), poliovirus (97.9%), and, in diphtheria-tetanus-acellular pertussis (DTaP) recipients, diphtheria (100%). However, responses to pertussis (25.0%), measles (66.7%), mumps (61.5%), hepatitis B (72.9%), and diphtheria in tetanus-diphtheria (Td) recipients (48.6%) were less favourable, with either only transient antibody responses or persistently negative titres. Factors associated with vaccine failure were older age at immunization; lower CD3, CD4 or CD19 counts; higher IgM concentrations; positive recipient cytomegalovirus serology; negative titres before immunization; acute or chronic graft-versus-host disease; and radiation during preconditioning. These response patterns and clinical factors can be used to formulate re-immunization and monitoring strategies. Patients at risk for vaccine failure should have long-term follow-up; those with loss of antibody response or no seroconversion should receive booster immunizations.     

Erythema multiforme minor following vaccination with paediatric vaccines

We present 2 cases of erythema multiforme following a combined tetanus and diphtheria revaccination and a combined diphtheria, tetanus, acellular pertussis inactivated polio and Haemophillus influenzae type B vaccine respectively, suggesting vaccines containing diphtheria and tetanus toxoids as a potential precipitating factor to erythema multiforme.     

Differences in reactogenicity and antigenicity of acellular and standard pertussis vaccines combined with diphtheria and tetanus in infants

Clinical and serological responses of infants to primary immunization with diphtheria-tetanus-pertussis (DTP) vaccine containing components of acellular pertussis vaccine (DTP-AC) were compared in a double-blind study with responses of infants receiving whole-cell DTP vaccine (DTP-WC). Three doses of either DTP-AC containing lymphocytosis-promoting factor (LPF) and filamentous hemagglutinin (FHA) or DTP-WC vaccine were given to infants at two, four, and six months of age. Nineteen infants received DTP-AC vaccine, and 20 infants received DTP-WC vaccine. Significantly more infants who received DTP-WC vaccine manifested fever, swelling, and/or total reactions than did infants who received DTP-AC vaccine. Infants who received DTP-AC vaccine had comparable antibody titers to LPF and significantly higher titers to FHA after three immunizations, as compared with the infants who received DTP-WC vaccine (P less than or equal to .001). The DTP-WC vaccine stimulated higher pertussis agglutination titers (P = .04) than did DTP-AC. The DTP-AC vaccine was immunogenic and significantly less reactogenic in infants than was the currently used DTP-WC vaccine.     

Seroepidemiologic study on pertussis, diphtheria, and tetanus in the Fukuoka area of southern Japan: seroprevalence among persons 0-80 years old and vaccination program

In Japan, mass vaccination for diphtheria, pertussis, and/or tetanus has been mandated by the Vaccination Law since 1948. In order to evaluate the efficacy of this vaccination policy, we conducted seroepidemiological studies on pertussis, diphtheria, and tetanus among individuals aged 0 - 80 years. The pertussis toxin seropositive rates of the vaccine-eligible groups and vaccine-ineligible groups were 55.0 and 57.9%, respectively. The seropositive rate of each group for diphtheria antitoxin was 76.3 and 75.7%, respectively. The tetanus antitoxin seropositive rates were 91.7 and 10.5%, respectively, showing a significant difference between the two groups (P < 0.001). For the three diseases, variations were seen between age groups in the geometric mean antibody titers due to changes of the vaccination program. The results of this study show that natural Bordetella pertussis infection has occurred more frequently than expected. In order to establish the most appropriate vaccination program for the control of pertussis, diphtheria, and tetanus in Japan, further evaluation is necessary.     

Expression of pertussis toxin correlates with pathogenesis in Bordetella species

Pertussis toxin is a principal determinant of virulence produced by Bordetella pertussis in the disease whooping cough and is the primary toxinogenic component of the pertussis vaccine. This toxin is not produced by the closely related species Bordetella parapertussis. Toxinogenic strains of B. parapertussis were constructed by the conjugative introduction of cloned pertussis toxin genes. These and analogous toxinogenic and nontoxinogenic strains of B. pertussis were assayed for their toxicity and reactogenic activities. Expression of active toxin by either Bordetella sp. correlated with the induction of leukocytosis, anaphylaxis, and histamine sensitivity.     

Efficacy of acellular pertussis vaccine

An outbreak of pertussis occurred in one room of a residential facility where 19 children aged 5 to 36 months were residing. They were prospectively surveyed to estimate the efficacy of acellular pertussis vaccine. Among the 19 residents, 9 were immunized with acellular pertussis vaccine. Among the 19 residents, 9 were immunized with acellular DTP vaccine and 10 were unimmunized. The spread of pertussis was surveyed bacteriologically and serologically for 2 months. Among the 9 immunized, 7 children acquired the laboratory-confirmed pertussis and 1 of the 7 developed the typical symptoms (whooping or paroxysmal coughing attack lasting for 14 days or more). Among the 10 unimmunized, 7 children acquired the laboratory-confirmed pertussis and 6 of the 7 developed the typical symptoms. There was no difference in the rate of secondary infection (7/9:7/10), but there was a significant difference in the rate of development of the typical symptoms (1/7:6/7 p less than 0.05). The point estimate of protective efficacy of the acellular DTP vaccine against typical pertussis was (6/10 - 1/9)/(6/10) x 100 = 81%. It was concluded from these findings that acellular DTP vaccine could not prevent the infection of Bordetella pertussis, but could prevent the development of the typical symptoms.