Haemophilus Influenzae Type B-tetanus Toxoid Research Articles

Immunogenicity of a Haemophilus influenzae type b–tetanus conjugate vaccine when administered separately or in combined vaccines for primary immunization in two consecutive national schedules in Turkey

In Turkey, the Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (Hib) was replaced by the combined diphtheria-tetanus-acellular pertussis and inactivated polio vaccine (DTaP-IPV/Hib) in 2008. This shift to the new schedule created different cohorts of vaccinated children as a consequence of the different schedules used. We evaluated the immunogenicity of the Hib vaccine in infants vaccinated with these different schedules. Three groups of children were evaluated: group 1 comprised 145 infants vaccinated with diphtheria, tetanus, and whole cell pertussis (DTwP), oral polio vaccine (OPV), and Hib vaccines simultaneously at separate sites; group 2 comprised 204 infants vaccinated with the DTaP-IPV/Hib combined vaccine; group 3 comprised 100 infants vaccinated with a mixed schedule of DTwP, OPV, and Hib for the first one or two doses, followed by DTaP-IPV/Hib vaccine to complete the series. Anti-polyribosylribitol phosphate (anti-PRP) titers ≥0.15μg/ml were similar in groups 1, 2, and 3. However, in group 1, who received all the vaccines at separate sites, ≥ l.0μg/ml long-lasting antibody titers and anti-PRP geometric mean titers were higher (p=0.001). This study showed that even one dose administered in combination with other vaccines in a primary series decreased the level of anti-PRP.

A comparative study to evaluate the safety and immunogenicity of two lots of Haemophilus influenzae type-B conjugate vaccine manufactured at different scales

ObjectiveTo compare the immunogenicity and safety of two different lots of SII Haemophilus influenzae type-B–tetanus toxoid conjugate (SII HibPRO) vaccine manufactured at different scales when given in 3-dose schedule. DesignPhase IV, open label, comparative, randomized parallel group study. SettingShirdi Sai Baba Hospital, Vadu Budruk, Pune and Pediatrics Department of King Edward Memorial Hospital Research Centre, Pune. Subjects204 normal healthy infants of age 6–8 weeks at the time of first vaccination. MethodsThe eligible subjects received 3 doses of 0.5ml of SII HibPRO vaccine of either lot depending upon randomization number, intramuscularly in right thigh in the EPI schedule of 6, 10 and 14 weeks. They also received concomitantly DTP-HB vaccine intramuscularly on left thigh and Oral Polio vaccine (OPV). Solicited reactions were captured for 7 days following each vaccination; the events beyond 7 days till day 28 were captured as unsolicited adverse events. Serious Adverse Events (SAEs) were looked for throughout the subject participation. Blood samples were collected at baseline (before the first dose) and one month after the third dose for anti-PRP (polyribosylribitol phosphate) antibodies. ResultsIn both groups, more than 98% subjects achieved short-term seroprotection (anti-PRP≥0.15μg/ml) after 3 doses. The long-term seroprotection (anti-PRP≥1μg/ml) was 87% and 80% in infants receiving lot manufactured at industrial scale and small scale respectively. Short and long term seroprotection and GMTs increased significantly as compared to baseline in both the groups. Overall local pain (52% and 58%), redness (30% and 41%), swelling (34% and 44%), fever (6% and 6%) and irritability (52% and 50%) were reported in infants receiving lot manufactured at industrial scale and small scale respectively. Majority of the reactions were mild and resoled without any sequelae. Four SAEs, none of them causally related to the study vaccine, occurred during study. ConclusionSII HibPRO vaccines manufactured in small and industrial scale are equally immunogenic, safe and confer adequate seroprotection to infants of 6–14 weeks of age. Scaling up production process has not affected the safety and immune response in the target population.

A new DTPw-HBV/Hib vaccine: Immune memory after primary vaccination and booster dosing in the second year of life

The response to booster vaccination at 15-18 months of age and the presence of immune memory in 10-month old children, primed with a new combined diphtheria-tetanus-hepatitis B- whole cell pertussis vaccine extemporaneously mixed with Haemophilus influenzae type b-tetanus toxoid conjugate (DTPw-HBV/Hib) from new antigen sources and containing 2.5µg polyribosyl-ribitol-phosphate (PRP) was assessed. Primary vaccination with the new DTPw-HBV/Hib vaccine was immunogenic and of comparable tolerability to commercially available Tritanrix™ HepB/Hiberix™. Children were boosted with DTPw-HBV, DTPw-HBV/Hib or separate DTPw-HBV+Hiberix™. Immune memory was assessed through administration of 10µg PRP polysaccharide. Anti-PRP antibody GMCs increased substantially after the challenge in DTPw-HBV/Hib-primed subjects indicating the presence of immune memory. One month after the booster dose, 100% of subjects had seroprotective antibody concentrations against PRP, diphtheria and tetanus, >95% were seroprotected against hepatitis B, ≥94.0% had a pertussis booster response. Substantial increases in antibody GMCs against all antigens were observed. Swelling >20 mm was the most common Grade 3 solicited symptom reported (up to 26.0% of subjects). Fever >39.5ºC was uncommon (

Immunogenicity and safety of four different doses of Haemophilus influenzae type b-tetanus toxoid conjugated vaccine, combined with diphtheria–tetanus–pertussis vaccine (DTP-Hib), in Indonesian infants

Widespread use of Haemophilus influenzae type b (Hib) conjugated vaccine in industrialized countries has resulted in a dramatic decline in the incidence of invasive Hib diseases, but the vaccine's cost has prevented its inclusion in basic immunization programs in developing countries. To overcome this problem, combination with diphtheria–tetanus–pertussis (DTP) vaccine or reduction in the dose of Hib vaccine has been proposed. To evaluate the immunogenicity and adverse reactions from lower doses of Hib-polyribosylphosphate (PRP) conjugated with tetanus toxoid (PRP-T), a double-blind study was conducted in Jakarta, Indonesia, and its suburbs. A total of 1048 infants 6 weeks to 6 months of age received three doses of DTP vaccine combined with the usual 10 μg dose or with a reduced dose of 5, 2.5 or 1.25 μg of PRP-T at two-monthly intervals. Antibodies were measured prior to the first dose and 4–6 weeks following the third dose. Adverse reactions were similar among all four groups. The only significant difference was a higher rate of irritability ( p < 0.02) and of temperature elevation >38 °C ( p < 0.009) after doses 1 and 2 in the lowest dose group (1.25 μg PRP-T) compared to the other groups. All participants tested had a 4-fold increase in antibodies against all DTP antigens. In addition, after a fourth booster dose of Hib, 99.6% of infants produced ≥0.15 μg/ml of antibody to Hib-PRP, and 96.4% showed levels ≥1.0 μg/ml after primary immunization, level that correlate with short- and long-term immunity, respectively. Antibody titers to the PRP antigen showed no significant differences among dosage groups with the exception of the 5.0 μg group, which had a significantly higher GMC than the 1.25 μg group ( p < 0.012). This study demonstrates that primary vaccination with half, one-fourth, or one-eighth of the usual dose of PRP-T, combined with DTP vaccine, produces protective immune responses, and has side effects that are comparable to DTP vaccination alone. In these lower dosages, PRP-T conjugate vaccine can lower vaccine costs to a level that is affordable for infant immunization programs in developing countries.

The effect of reconstitution of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) vaccine on the immune responses to a diphtheria–tetanus-whole cell pertussis (DTwP) vaccine: a five-year follow-up

Controversial results have been obtained from previous studies on the combined administration of Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria–tetanus-whole-cell pertussis (DTwP) combination vaccines, with regard to possible reciprocal interference between the constituent antigens. To document the priming effect and possible long-term immunogenic interference of PRP-T and DTwP combination vaccines, a randomized, double-blind, controlled study was conducted in Belgium. A total of 168 healthy infants received, at 3, 4 and 5 months of age, DTwP vaccine mixed just prior to injection either with PRP-T vaccine (group A, DTwP//PRP-T, N=85) or with placebo (group B, DTwP//Placebo, N=83). At the age of 14 months, children of both groups were randomized to receive either a dose of DTwP//PRP-T vaccine (subgroups A1 and B1) or a dose of Hib polysaccharide (PRP) vaccine (subgroups A2 and B2). Those children in subgroups A1 and B1 had an additional serum sample taken at the age of 5 years (at the time of a DT booster). The immune response to Hib polysaccharide at the age of 4, 5 and 6 months confirmed the excellent immunogenicity profile of PRP-T in infants. In addition, the vigorous anamnestic response (i.e. a 20-fold increase of GMT) to a booster dose of the plain capsular polysaccharide (PRP) reflected the efficient Hib-priming induced by the combined DTwP//PRP-T vaccine. Reconstitution of PRP-T with DTwP did not affect the immune response to diphtheria toxoid or pertussis agglutinins. Nevertheless, at almost any time point during the five-year follow-up, the tetanus antitoxin GMT values were significantly lower in the DTwP//PRP-T group (A and A1) than in the DTwP//Placebo group (B and B1). Despite the suppressive effect on GMT values, intergroup differences in rates of seroprotection were never significant, except after doses 2 and 3 for which there were lower percentages of children in group A with antitoxin titers >0.05 IU/mL and >1.0 IU/mL. In the group primed with the combined DTwP//PRP-T vaccine, (1) a DT booster dose at the age of 5 years provoked a 150-fold increase in tetanus antitoxin GMT, (2) a high tetanus antitoxin GMT value was attained (GMT=19.3 IU/mL) and (3) all children in this group had tetanus antitoxin titers >1.0 IU/mL, so it may be concluded that all these children will still be protected against tetanus until at least the age of the next recommended booster dose (i.e. the age of 15 years). No differences in the occurrence of adverse events were observed between the groups who received the DTwP//PRP-T vaccine or the DTwP//Placebo vaccine, both vaccines being associated with events customarily attributable to DTwP (data not shown). Our results indicate (1) that the combination vaccine, DTwP//PRP-T, represents a safe and effective alternative for the existing uncombined vaccines and (2) that the long-term effect of interference between the components of future combination vaccines should be studied with subsequent booster doses, followed by the evaluation of persistence of antibodies over several years.

Priming effect, immunogenicity and safety of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular pertussis (DTaP) combination vaccine administered to infants in Belgium and Turkey

To evaluate the priming effect, immunogenicity and safety of an Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-acellular (two component) pertussis (DTaP) combination vaccine, a randomized, comparative study was conducted in two centers, one in Belgium and one in Turkey. A total of 410 healthy infants, 160 in Belgium and 250 in Turkey, randomly received DTaP and PRP-T vaccines in one of three fashions. One group ( N=138) received DTaP and PRP-T vaccines reconstituted immediately prior to injection at 3, 4 and 5 months of age, and are referred to as the combined, short schedule group (Co-S). A second group ( N=135) received DTaP+PRP-T simultaneously but injected at different sites according to the same schedule, and are referred to as the associated, short schedule group (As-S). The third group ( N=137) also received DTaP+PRP-T at separate sites, but at 2, 4 and 6 months, and are referred to as the associated, long schedule group (As-L). The As-L group allowed for serological bridging with a Senegalese two-component pertussis vaccine efficacy trial, using the same batch of DTaP vaccine. Children of both short-schedule groups (Co-S and As-S) received, at the age of 12–14 months, a booster dose of DTaP vaccine associated with unconjugated PRP vaccine. Mixing of the vaccines did not affect the immune response to the antigens included in the DTaP vaccine. The immune response to Hib capsular polysaccharide, however, was significantly lower after combined administration (Co-S group) than after associated (As-S group) administration ( P<0.0001), with a similar trend among both countries (GMTs, 1.78 μg/ml and 6.19 μg/ml in Belgium, and 5.02 μg/ml and 11.67 μg/ml in Turkey). Booster vaccination with the unconjugated PRP induced a vigorous and similar anamnestic response in both groups. Belgian infants showed a significantly lower immune response to all antigens than Turkish infants ( P⩽0.001 for all antigens), with a similar trend among each study group. In all groups, the incidence of adverse events was lower than that usually reported after DTwP(whole-cell) vaccine. Higher rates of systemic reactions were observed in the Belgian population, possibly due to differences in reporting practice. Our results indicate (1) that the combination vaccine, DTaPPRP-T, represents an important improvement over the existing uncombined vaccines; (2) that immunogenicity studies should include at least one booster injection to evaluate priming effects by combined vaccines; and (3) that it is feasible and valuable to co-randomize combination vaccine studies in sufficiently different geographical areas and child populations.

Safety and immunogenicity of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-pertussis (DTP) combination vaccine administered in a dual-chamber syringe to infants in Belgium and Chile

To document any unexpected differences in the immune response between study populations and to evaluate immunogenicity and safety of a simplified presentation (dual-chamber syringe) of an Haemophilus influenzae type b-tetanus toxoid conjugate (PRP-T) and diphtheria-tetanus-pertussis (DTP) combination vaccine, a multicentre, randomized, comparative study was conducted in Belgium and Chile. A total of 537 healthy infants, 270 in Chile and 267 in Belgium, received PRP-T and DTP vaccines combined in a dual-chamber syringe (D-Ch group, DTP PRP-T , reconstituted by pressing the plunger of the syringe immediately before injection, n = 239) or combined in a single-chamber syringe (C-In group, DTP//PRP-T, reconstituted immediately before injection, n = 61) or in separate injections (S-In group, DTP+PRP-T, simultaneously injected at separate sites, n = 237) at 3, 4, and 5 months of age. Serum samples were collected before vaccination and at 6 months of age. In the D-Ch group, the incidence of adverse events was comparable to administration of DTP vaccine alone. Higher rates of local and systemic reactions were observed in the Chilean population, possibly due to differences in surveillance practice. The immune response to each vaccine component compared well to that of the separate administration of PRP-T and DTP vaccines, except for higher post-immunization anti-PRP geometric mean titre (GMT) values after separate injections (25.6 μg mL −1) than after combined injection with the dual-chamber syringe (17.6 μg mL −1) ( p = 0.001). An unexpected ‘syringe’ effect was seen: a greater post-immunization anti-PRP GMT was observed in the D-Ch group (17.6 μg mL −1) than in the C-In group (7.7 μg mL −1) ( p = 0.0001). Whereas pre-immunization GMTs of some antibodies were significantly lower in Chilean than in Belgian infants, the post-immunization GMTs of Chilean infants were two to three times greater for all of the antibodies studied ( p < 0.005). Differences in reactogenicity and in the immune response between the study populations or the different vaccine presentations were striking, but are probably of no clinical relevance. The convenient dual-chamber syringe presentation of DTP and PRP-T vaccines is safe and highly immunogenic.

Factors associated with superior antibody responses to a single dose of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine administered to Chilean infants at 2 months of age

The anticapsular antibody response of Chilean infants to a single dose of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate vaccine is substantially higher than that observed among infants of similar age from the USA. Comparison of selected demographic and environmental factors indicates that low maternal education and a greater number of persons in the home are significantly associated with the superior responder phenotype. High anticapsular antibody responses were associated with high antibody responses to tetanus toxoid, the carrier protein in this conjugate, but not to diphtheria toxoid. These data suggest that environmental factors may enhance the magnitude of the primary antibody response to PRP-T vaccine.

Passively acquired anti-tetanus and anti-Haemophilus antibodies and the response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy.

To study the influence of maternally inherited tetanus antitoxin (anti-TT) antibodies on the response to the Haemophilus influenzae type b (Hib) capsular polysaccharide (PS)-tetanus toxoid conjugate (PRP-T) vaccine. One hundred thirty healthy infants received their first dose of PRP-T in the same syringe with diphtheria-tetanus-pertussis vaccine (DTP) at 1 to 2 months, and 66 of them received a second dose at 3 to 4 months of age. Maternal anti-TT antibodies did not interfere with the anti-Hib PS response to the first PRP-T vaccination; the geometric mean concentration (GMC) of anti-Hib PS was 0.14 microgram/ml in those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 15) and 0.13 microgram/ml in those with the highest anti-TT (> or = 3 IU/ml, n = 25). After the second dose of PRP-T there was a positive correlation (r = 0.37, P = 0.004) between the anti-Hib PS response and the preimmunization anti-TT; those with the lowest preimmunization anti-TT (< 0.3 IU/ml, n = 9) achieved GMC of anti-Hib PS of 1.22 micrograms/ml and those with anti-TT > or = IU/ml (n = 22) anti-Hib PS GMC of 2.67 micrograms/ml. High preimmunization anti-Hib PS antibodies did not interfere with the final antibody concentrations; the GMC of anti-Hib PS after the second dose of PRP-T was 1.60 micrograms/ml in those with a preimmunization titer > or = 1.0 microgram/ml (n = 12) and 1.57 micrograms/ml in those with a titer of < 1.0 microgram/ml (n = 53). The data suggest that infants can be safely vaccinated with PRP-T even though they have received high concentrations of anti-TT from their mother.

Clinical and immunologic responses to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants injected at 3, 5, 7, and 18 months of age

The safety and immunogenicity of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (Hib-TT) were evaluated in 77 healthy infants receiving injections at 3, 5, 7, and 18 months of age. No serious local or systemic reactions were noted. After the first injection the geometric mean Hib antibody level rose to 0.55 micrograms/ml, and each subsequent injection elicited a statistically significant rise in the geometric mean. The percentage of vaccinees with Hib antibody levels greater than 0.15 micrograms/ml serum was 75.5% after the first, 97.4% after the second, and 100% after the third Hib-TT injection. This percentage fell to 90.9% at 18 months of age but rose again to 100% after the fourth injection. Control infants (n = 10) injected with diphtheria-tetanus toxoid-pertussis vaccine only had nondetectable levels after the second injection. Hib-TT elicited increases of Hib antibody in all isotypes: IgG greater than IgM greater than IgA. Among IgG subclasses the highest increases were of IgG1. All vaccinated subjects had greater than 0.01 U/ml of TT antibody (estimated protective level) throughout the study. We conclude that Hib-TT, injected at 3, 5, 7, and 18 months, is safe and induces protective levels of antibodies during the age of highest incidence of meningitis caused by Hib.