Immunogenicity of a combined diphtheria-tetanus-acellular pertussis vaccine in adults

Two clinical studies were undertaken to evaluate the immunogenicity of an adult-type dTpa booster vaccine (Boostrix by GlaxoSmithKline Biologicals). Blood samples taken prior to vaccination showed that 24.4 and 13.0% of subjects were seronegative for diphtheria and tetanus antibodies, respectively. Moreover, about one-third of the vaccinees had no detectable levels of antibodies to pertussis toxoid (PT) or pertactin (PRN). One month post-vaccination, more than 93% of all individuals, regardless of age or type of vaccine received, had seroprotective antibody levels for diphtheria and tetanus (> or = 0.1IU/ml). In those individuals vaccinated with the adult-type dTpa vaccine (Boostrix), more than 98% were found to be seropositive for antibodies to all three pertussis antigens (PT, filamentous haemogluttin (FHA), and PRN). These data suggest that immunity to diphtheria, tetanus and pertussis (DTP) in adults wanes and that booster vaccination with an adult-type combined dTpa vaccine would boost the serological response to diphtheria antitoxin, tetanus antitoxin and antibodies to Bordetella pertussis PT, FHA and PRN.     

A randomised controlled trial with a diphtheria-tetanus-acellular pertussis (dTpa) vaccine in adults

The aim of this assessor-blinded trial was to compare the immunogenicity and reactogenicity of a candidate diphtheria, tetanus toxoids and acellular pertussis vaccine with reduced antigen content for diphtheria and pertussis (dTpa) with a licensed reduced adult-type diphtheria-tetanus vaccine Td (reduced diphtheria content) and with an experimental candidate monovalent acellular pertussis vaccine with reduced antigen content (pa). The dTpa and pa vaccines had identical pertussis antigen content. A total of 299 healthy adults (> or =18 years, mean age: 30.1 years+/-10.7) were randomised into 3 groups to receive a single dose of one of the study vaccines. In all groups, clinically significant reactions (severe) were infrequent (0-6%) and no serious adverse events were reported during the study. The incidence of local and systemic reactions following the administration of dTpa was comparable to the Td vaccine group. Of the total study group, prior to vaccination 52. 3 and 93.2% of the subjects had anti-diphtheria and anti-tetanus antibody levels > or = 0.1 IU/ml, respectively; and 73.1, 98.2 and 74.5% of the subjects were seropositive for pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) antibodies, respectively. One month after vaccination, a similar percentage of subjects in the dTpa and Td groups had anti-diphtheria (88.4% vs 90. 1%) and anti-tetanus (100% vs 98.9%) antibody levels > or =0.1 IU/ml. Similar anti-FHA (100%) and anti-PRN (98.9%) vaccine response rates were seen in the dTpa and pa groups, while the anti-PT vaccine response rates were 96.8 and 100.0%, respectively. The dTpa vaccine is as well tolerated and immunogenic as the licensed Td vaccine, and additionally, can also boost antibodies against pertussis.     

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.     

Immunogenicity and reactogenicity of combined acellular pertussis/tetanus/low dose diphtheria vaccines given as a booster to UK teenagers

Sustained high incidence of pertussis, particularly amongst unvaccinated infants, is of concern. Inclusion of pertussis vaccination with tetanus and low dose diphtheria (Td) teenage boosters may protect individuals through reproductive years, and prevent transmission to offspring. UK teenagers who had previously received only a three-dose primary course of whole cell pertussis vaccination in infancy and who were due to receive a Td booster (n=323) were randomised to four groups: Td, TdaP, TdaP-inactivated polio vaccine (IPV) (Aventis Pasteur), TdaP (GlaxoSmithKline). There were significant pre- to post-vaccination GMC and GMFR increase for vaccine-contained pertussis antigens (p<0.001) in recipients of aP-containing vaccine. All groups demonstrated significant increases pre- to 4 weeks post-vaccination in diphtheria (D)/tetanus (T) geometric mean concentrations (GMCs) and fold rises (GMFRs) (p<0.001). Groups all achieved similar D and T post-vaccination GMCs. Local reactogenicity was generally similar between groups and was not associated with pre-booster diphtheria/tetanus antibody levels. A minority of vaccinees reported systemic symptoms with similar proportions between groups for each symptom assessed. This study demonstrated that addition of aP and/or IPV to Td vaccine did not materially alter reactogenicity or immunogenicity of Td components, and induced immune responses to pertussis antigens in teenagers who had received no pertussis vaccine since infancy.     

Enhanced sensitisation of mice with diphtheria tetanus acellular pertussis vaccine to local swelling reaction to the booster immunisation

Severe local swelling has been regarded as a serious safety problem for the booster immunisations of diphtheria tetanus acellular pertussis combined (DTaP) vaccine and DT combined toxoids (DT-td). We attempted to search for the factor of DTaP vaccines possibly contributing to the enhanced local reaction by using the mouse hind paw swelling reaction. Mice were immunised intramuscularly with DTaP vaccine twice at 1-month interval and were challenged their hind paw with one of the antigens of DTaP vaccine 2 weeks later. D-td was shown to elicit the strongest swelling among the vaccine antigens. No causal relationship was found between the swelling and the level of immunoglobulin G (IgG) or IgE in mice. Residual pertussis toxin (PT) activity of DTaP vaccines for immunisation was shown to play a role in the enhanced sensitisation of mice to the D-td-related hind paw swelling.     

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

BackgroundIn a prospective, randomized pivotal phase III clinical trial, the immunogenicity and reactogenicity of a tetanus-diphtheria-acellular pertussis vaccine (Tdap) and a tetanus-diphtheria vaccine (Td) vaccine were studied in participants aged 11–64 years. Here we report antibody persistence through 10 years after vaccination.MethodsParticipants who received Tdap or Td in the original phase III trial and provided pre- and post-vaccination serum samples were recruited to donate sera at 1, 3, 5 and 10 years post-vaccination. Antibody concentrations were measured using standard assay techniques.ResultsInitially, 1457 Tdap and 1152 Td recipients were included; of these, 175 persons from Tdap group were available at the final study bleed point. Nearly all adolescents in both groups had diphtheria antibody levels ≥0.1 IU/mL 1 month after vaccination, which were maintained in ≥95% of vaccinees at 5 and 10 years. Among adults, ≥94% had diphtheria antibody levels ≥0.1 IU/mL 1 month after vaccination, which were maintained in ≥80% at 5 and 10 years. Nearly all participants had tetanus antibodies ≥0.1 IU/mL throughout the study. PT antibodies declined to pre-vaccination levels approximately 5 years post-vaccination; FHA, PRN and FIM antibodies waned at 5 and 10 years but remained several-fold higher than pre-vaccination levels.ConclusionsTdap and Td provide long-lasting protective immune responses against diphtheria and tetanus. Pertussis antibodies following Tdap generally exceeded pre-vaccination levels throughout the study, but showed substantial waning. These data may inform discussion of the need for repeat Tdap booster vaccinations among adults.Trial registrationThe original phase III clinical trial, as well as the 1-, 3-, and 5-year serology follow-up studies were conducted prior to mandatory registration. The 10-year serology follow-up data collection was performed as part of a repeat Tdap administration clinical trial that was registered under clinicaltrials.gov number NCT01439165.     

国产吸附无细胞白百破联合疫苗的免疫持久性

目的探讨国产吸附无细胞白百破联合疫苗（DTaP）的免疫持久性。方法选择无接种禁忌证、3月龄未接种DDT的健康婴儿,采用随机、双盲、同类疫苗平行对照设计的方法,将受试者分为2组,分别接种甲、乙2个生物制品研究所生产的DTaP,全程免疫后1个月、1年采静脉血,白喉抗体（DT）、破伤风抗体（TT）测定采用间接血凝法。抗百日咳毒素抗体（PT）和抗丝状血凝素抗体（FHA）采用酶联免疫吸附试验ELISA方法。结果DTaP全程免疫1年后,DT、TT、PT、FHA抗体GMT均维持在较高水平,与免后1个月抗体GMT差异无统计学意义（P〉0.05）;2家生物制品研究所DTaP免疫原性（免后1个月、1年）比较,差异无统计学意义（P〉0.05）。结论国产DTaP疫苗安全,免疫原性强,质量稳定,纳入国家免疫规划后将有效控制相关疾病的发生和流行。     

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N=310, Td+pa group N=77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.     

Trial of a new acellular pertussis vaccine in healthy adult volunteers

Immunogenicity and reactogenicity of a new acellular pertussis vaccine were tested in healthy adults. The vaccine contained three constituents of Bordetella pertussis; filamentous haemagglutinin, pertussis toxin (PT) and fimbriae bearing agglutinogens 2 and 3. The constituents were separately purified, treated with formaldehyde and combined with one of two aluminium adjuvants. Subjects received one dose of vaccine or an appropriate adjuvant-only preparation and were monitored for clinical responses for 7 days. Results with the two forms of vaccine were similar. Of 35 vaccinees, none had a temperature higher than 37 degrees C or a severe reaction, one had a moderate reaction (possibly due in part to intercurrent infection) and nine had mild reactions confined to localized discomfort and/or erythema or induration at the injection site. All vaccinees had good serum antibody responses to vaccine antigens measured by ELISA and for PT, by neutralization of its effects on Chinese hamster ovary cells.     

A randomised, double-blind, non-inferiority clinical trial on the safety and immunogenicity of a tetanus, diphtheria and monocomponent acellular pertussis (TdaP) vaccine in comparison to a tetanus and diphtheria (Td) vaccine when given as booster vaccinations to healthy adults

Background

Increasing incidence of pertussis in adolescents and adults has stimulated the development of safe and immunogenic acellular pertussis vaccines for booster vaccination of adolescents and adults.

Purpose

To obtain clinical documentation of the safety and immunogenicity of a tetanus, diphtheria and monocomponent acellular pertussis combination vaccine (TdaP), when given as a booster vaccination to adults.

Methods

The trial was double-blind, controlled and randomised. 802 healthy adults, aged 18–55 years who had completed childhood vaccination with diphtheria, tetanus and whole cell pertussis vaccine (DTwP), were booster vaccinated with TdaP or Td. Blood samples were taken before and one month after the vaccination for serological analysis and adverse events were recorded during the one-month-follow-up period.

Results

The monocomponent acellular pertussis vaccine (aP) in the TdaP vaccine was immunogenic in adults with 92.0% of TdaP vaccinated subjects obtaining an anti-pertussis toxin (anti-PT) antibody booster response. TdaP was non-inferior to Td in eliciting seroprotective anti-tetanus and diphtheria antibody concentrations with more than 98% of subjects obtaining post-vaccination seroprotective concentrations (≥0.1 IU/mL). T and d booster response rates were 93.0% and 97.5%, respectively.The frequencies of solicited local adverse reactions were low and comparable between TdaP and Td vaccinees. In the TdaP group, 30.7% reported pain, 4.2% swelling and 2.0% erythema at the injection site. The most frequent solicited general symptoms were headache (20.4%), fatigue (17.0%) and myalgia (10.0%). In the Td group, 35.7% reported pain, 2.5% swelling and 3.2% erythema at the injection site, whereas headache, fatigue and myalgia were reported by 15.7%, 14.5% and 12.5%, respectively.In conclusion, TdaP Vaccine SSI was safe and immunogenic when given as a booster vaccination to adults. ClinicalTrials.gov registration number: NCT01033877.     

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N = 310, Td + pa group N = 77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.     

Booster vaccination of adults with reduced-antigen-content diphtheria,Tetanus and pertussis vaccine: Immunogenicity 5 years post-vaccination

At 60 months post-vaccination, adults (mean age 45.6 years) randomised to receive combined reduced-antigen-content diphtheria–tetanus and acellular pertussis vaccine (dTpa) versus tetanus–diphtheria (Td) + monovalent acellular pertussis (pa) were seroprotected against diphtheria (≥0.016 IU/mL Vero cell assay) and tetanus (≥0.1 IU/mL ELISA assay) in 94.4% and 96.2%, respectively (dTpa), compared with 93.7% and 90.6% (Td + pa). Anti-FHA, anti-PT and anti-PRN antibodies (≥5 EL.U/mL) were maintained in 100%, 89.5% and 95.0% of dTpa versus 100%, 85.5% and 90.6% of pa vaccine recipients. At 5 years post boosting, antibody levels to diphtheria and tetanus are similar amongst adults receiving a dTpa or dT, and pertussis antibodies remain above pre-booster levels in at least 85%.     

Immunogenicity and safety of a tetanus toxoid,reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age

Purpose

This study was conducted to assess the immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine containing three pertussis antigens (Boostrix^®, Tdap3v), currently licensed in the US for use in adolescents 10–18 years of age, in adults 19–64 years of age.

Methods

2284 healthy adults, aged 19–64 years, were randomized to receive a single dose of Tdap vaccine, either Tdap3v or a five-pertussis component Tdap vaccine (Adacel^®, Tdap5v) licensed for adult use in the US. Blood samples were taken before and 1 month after vaccination. Reactogenicity was assessed for 15 days after vaccination.

Results

Tdap3v was comparable to Tdap5v in eliciting seroprotective levels of antibodies to diphtheria and tetanus toxoids, with >98% of subjects having post-vaccination seroprotective antibody levels (≥0.1 IU/mL) against diphtheria or tetanus toxoids. The pertussis components of Tdap3v were shown to be immunogenic in adults, with booster responses to pertussis toxoid (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) observed in 77.2%, 96.9%, and 93.2%, respectively, of Tdap3v recipients, and in 47.1%, 94.0%, and 91.7%, respectively, of Tdap5v recipients. Anti-pertussis antibody GMCs in Tdap3v recipients exceeded those observed in infants following primary DTaP vaccination, in whom efficacy against pertussis disease was subsequently demonstrated. Injection site reactions (pain, redness, and swelling) and fever ≥37.5 °C (99.5 °F) were reported significantly more often (p < 0.05) by Tdap5v recipients than by Tdap3v recipients. Fatigue preventing normal daily activities was reported by a small but significantly greater percentage of Tdap3v recipients (2.5%) than Tdap5v recipients (1.2%, p < 0.05).

Conclusion

In adult recipients, Tdap3v was comparable to an approved Tdap vaccine in providing seroprotection against diphtheria and tetanus, and produced immune responses to pertussis antigens consistent with protection against disease. The overall safety profile of Tdap3v was generally comparable to that of Tdap5v [NCT #106316].     

Phase I clinical trial of an acellular pertussis vaccine composed of genetically detoxified pertussis toxin combined with FHA and 69 kDa.

An acellular pertussis vaccine composed of genetically detoxified pertussis toxin (PT-9K/129G), filamentous haemagglutinin (FHA) and pertactin (69 kDa protein) was evaluated in adult volunteers, in double blind, versus placebo. No fever was reported in either group. Mild local reactions were reported after injection of both vaccine and placebo. After the first dose a marked increase in antibodies to PT, FHA and 69 kDa protein was seen in vaccinated subjects with the exception of one who responded well to PT and FHA but did not show a humoral response to the 69 kDa protein. All vaccinees acquired cellular immunity against the three antigens. No significant variation was observed in the humoral or cellular responses after the second dose.     

Effect of injection site on reactogenicity and immunogenicity of acellular and whole-cell pertussis component diphtheria-tetanus-pertussis vaccines in infants

The effect of injection site on reactogenicity and specific immunogenicity was assessed in participants in a pertussis vaccine efficacy trial. The percent of DTwP and DTaP recipients with any reaction was slightly lower in subjects injected in the buttock compared with those injected in the thigh. This finding was most common in DTwP recipients. Geometric mean antibody values to pertactin, filamentous hemagglutinin and fimbriae (Bordetella pertussis antigens) were lower in DTaP vaccinees when buttock was utilized as the injection site. Our findings present evidence against the use of the buttock as the site of immunization for DTaP vaccines since the benefit with regards to reactogenicity is minimal and the immunologic response to an important antigen of B. pertussis, pertactin, is decreased.     

Anti-pertussis antibody kinetics following DTaP-IPV booster vaccination in Norwegian children 7–8 years of age

At the age of 7–8 years a booster of diphtheria, tetanus, acellular pertussis and polio vaccine is recommended for children in Norway. In this cross-sectional study we have analysed the antibody levels against pertussis vaccine antigens in sera from 498 children aged 6–12 years. The purposes of this study were to investigate the duration of the booster response against the pertussis vaccine antigens pertussis toxin (PT) and filamentous haemagglutinin (FHA); to determine the presence of high levels of pertussis antibodies in absence of recent vaccination; and to analyse how booster immunisation may interfere with the serological pertussis diagnostics. Prior to the booster the IgG antibody levels against PT revealed a geometric mean of 7.3 IU/ml. After the booster the geometric mean peak anti-PT IgG response reached to 45.6 IU/ml, followed by a steady decline in antibody levels over the next few years. The IgG anti-FHA levels followed the anti-PT IgG profiles. Three years after the booster the geometric mean IgG levels were only slightly above pre-booster levels. Prior to the booster 44% of the sera contained ≤5 IU/ml of anti-PT IgG compared to18% 3 years after and 30% 4 years after the booster. When recently vaccinated children were excluded, 6.2% of the children had anti-PT IgG levels above 50 IU/ml which may indicate pertussis infection within the last 2 years. This study indicates that the currently used acellular pertussis vaccines induce moderate immune responses to the pertussis antigens and that the antibodies wane within few years after the booster. This lack of sustained immune response may partly be responsible for the increased number of pertussis cases observed in this age group during the last years.     

A search for serologic correlates of immunity to Bordetella pertussis cough illnesses

In a pertussis vaccine efficacy trial in Germany we collected sera from vaccinees (DTaP or DTP) after the third and fourth doses of vaccine or at comparable time periods in DT vaccine recipients. In addition, sera were collected from a randomized sample of subjects in each vaccine group at approximately 3-month intervals from which antibody kinetic curves were constructed, which allowed us to estimate specific antibody values to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin and fimbriae-2 at the time of exposure in the household setting. The imputed geometric mean antibody values to PT, pertactin and fimbriae-2 at the time of household exposure to Bordetella pertussis infection were higher (p < 0.07 or lower) in non-cases compared with cases. A multivariate (classification tree) analysis found that only pertactin and PT were significant in protection. Subjects with an imputed pertactin value of < 7 EU ml⁻¹ had a 67% (18/27) chance of infection regardless of the PT value. If the pertactin value was ≥ 7 EU ml⁻¹ and the PT value ≥ 66 EU ml⁻¹ all subjects were non-cases. If the pertactin value was ≥ 7 and the PT value was < 66 EU ml⁻¹ the predicted probability of being a case was 31% (15/49). Logistic regression analysis also found that high versus low pertactin values were associated with illness prevention following household exposure. In the presence of antibody to pertactin, PT and fimbriae-2, the additional presence of antibody to FHA did not contribute to protection. Our data support historical data indicating that agglutinating antibodies are associated with protection and also recent serologic correlates data and clinical efficacy data which indicate that multicomponent vaccines containing pertactin and fimbriae have better efficacy than PT or PT/FHA vaccines.     

Immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV) compared to separate administration of standalone DTaP and IPV vaccines: a randomized, controlled study in infants in the Republic of Korea

This randomized trial enrolled 442 infants in the Republic of Korea to assess the immunogenicity and safety of a combined diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine (DTaP-IPV; Tetraxim™) for primary vaccination at 2, 4 and 6 months of age compared with DTaP and IPV vaccines given separately. Immunogenicity was high in both groups; seroprotection and seroconversion rates of the combined vaccine (Group A) were non-inferior to the control vaccines (Group B). All subjects were seroprotected against poliovirus types 1, 2 and 3 (≥8 1/dil) and anti-diphtheria (≥0.01 IU/mL); 99.0% were seroprotected against tetanus (≥0.1 IU/mL). At least 93.6% had anti-diphtheria antibody titers ≥0.1 IU/mL. Anti-pertussis toxoid (PT) and anti-filamentous haemagglutinin (FHA) seroconversion (≥4-fold increase in antibody titer) rates were 96.6% and 94.4% for Group A, 92.2% and 78.4% for Group B. Most solicited reactions occurred within 4 days of vaccination, resolved within 3 days and were mild. Severe solicited reactions occurred after ≤0.5% of doses in Group A and ≤0.9% in Group B. No withdrawals occurred because of adverse events. The DTaP-IPV combined vaccine given at 2, 4, and 6 months of age was well tolerated; immunogenicity was similar to the control vaccines.     

Safety and immunogenicity of combined diphtheria-tetanus-pertussis (whole cell and acellular)-Haemophilus influenzae-b conjugate vaccines administered to Indonesian children

A randomized double-blind trial was conducted to evaluate the safety and immunogenicity of vaccines comprised of diphtheria (D) and tetanus (T) toxoids combined with either a whole cell (P) or an acellular (aP) pertussis component and Haemophilus influenzae type b polyribosylphosphate (PRP) tetanus toxoid conjugate (PRP-T) in Indonesian infants. Three doses of either DTaP, DTaP-PRP-T, or DTP-PRP-T were administered to 930 infants approximately 2-3 months of age and at 2 month intervals thereafter. A booster dose of either DTP-PRP-T or DTaP-PRP-T was administered at 15-18 months of age. Both local and systemic reactions occurred at a significantly (p < 0.001-0.026) higher rate in the group that received whole cell pertussis vaccine versus groups which were immunized with aP containing vaccines. There was no significant difference (p > 0.05) in the rate of adverse events between groups immunized with DTaP or DTaP PRP T. One month after the third dose of vaccine, 99% of subjects had achieved > or =0.1 IU of anti-D and anti-T antibody per ml of serum. The geometric mean titer (GMT) to D was significantly (p < 0.001) higher in the group immunized with DTaP versus the other two groups whereas the anti-T GMT was significantly (p < 0.006) higher for the group immunized with DTP-PRP-T. Both the anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibody levels were significantly (p < 0.001) higher in recipients of acellular versus whole cell pertussis vaccine. In contrast, the anti-B. pertussis agglutinating antibody response was significantly (p < 0.0001) higher in the group immunized with whole cell pertussis vaccine. The anti-PRP GMTs (microg antibody/ml) at 7 months were 0.096, 3.35 and 6.11 for groups immunized with DTaP, DTaP-PRP-T and DTP-PRP-T, respectively. The GMT for those immunized with DTP-PRP-T was significantly (p < 0.001) higher compared to recipients of DTaP-PRP-T. The percent of children who attained > or =0.15 or > or =1 microg/ml after immunization was 18 and 2% for the DTaP group, 93 and 76% for the DTaP-PRP-T group and 97 and 88% for the DTP-PRP-T group. At the > or =1 microg/ml level the difference between the DTaP-PRP0-T and DTP-PRP-T groups was significant (p < 0.01). Children immunized with either DTaP, DTaP-PRP-T, or DTP-PRP-T were reimmunized with DTaP-PRP-T whereas a portion of children immunized with DTP PRP T where also boosted with this vaccine at 15-18 months of age. There was a vigorous anamnestic response to the D and T components with all children possessing > or =0.1 IU/ml. There was also a substantial increase in anti-PT, anti-FHA and B. pertussis agglutinating antibodies. The poorest anti-PT response was seen among children receiving DTP-PRP-T for both primary and reimmunization while the highest agglutinating antibody response followed receipt of 4 doses of DTP-PRP-T. Greater than 80% of children immunized with either DTP PRP T or DTaP-PRP-T possessed > or =0.15 microg/ml before boosting versus 38% for those vaccinated with DTaP (p < 0.001). Primary immunization with DTP-PRP-T resulted in a significantly (p < 0.05) higher percentage (72%) maintaining > or =1 microg/ml compared to those immunized with DTaP-PRP-T (46%). Prior to reimmunization, the anti-PRP GMT was significantly (p < 0.005) higher for children immunized with 3 doses of DTP-PRP-T versus DTaP-PRP-T. Subsequent to reimmunization, > or =95% of subjects attained > or =1 microg/ml.     

Recombinant cholera toxin B subunit (rCTB) as a mucosal adjuvant enhances induction of diphtheria and tetanus antitoxin antibodies in mice by intranasal administration with diphtheria-pertussis-tetanus (DPT) combination vaccine

Recombinant cholera toxin B subunit (rCTB) which is produced by Bacillus brevis carrying pNU212-CTB acts as a mucosal adjuvant capable of enhancing host immune responses specific to unrelated, mucosally co-administered vaccine antigens. When mice were administered intranasally with diphtheria-pertussis-tetanus (DPT) combination vaccine consisting of diphtheria toxoid (DTd), tetanus toxoid (TTd), pertussis toxoid (PTd), and formalin-treated filamentous hemagglutinin (fFHA), the presence of rCTB elevated constantly high values of DTd- and TTd-specific serum ELISA IgG antibody titres, and protective levels of diphtheria and tetanus toxin-neutralizing antibodies but the absence of rCTB did not. Moreover, the addition of rCTB protected all mice against tetanic symptoms and deaths. DPT combination vaccine raised high levels of serum anti-PT IgG antibody titres regardless of rCTB and protected mice from Bordetella pertussis challenge. These results suggest that co-administration of rCTB as an adjuvant is necessary for induction of diphtheria and tetanus antitoxin antibodies on the occasion of intranasal administration of DPT combination vaccine.