Persistence of serum antibodies elicited by Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants vaccinated at 3, 5 and 12 months of age

Eighty-five children received three injections of a vaccine consisting of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) conjugated to tetanus toxoid (TT) (Hib-TT) at 3, 5 and 12 months of age according to the vaccination schedule for Swedish children. Diphtheria-tetanus toxoid vaccine was concurrently injected at another site. Two dosages, 7.5 and 15 micrograms, of Hib CPS were studied. No serious reactions occurred. Hib-TT elicited fewer local reactions than diphtheria-tetanus toxoid vaccine. Significant increases in Hib CPS serum antibodies occurred after all injections in both dosage groups with virtually no differences between the two groups. After the first and second injections geometric mean serum antibody concentrations of both dosage groups combined increased to 0.49 and 3.71 micrograms/ml and 81 and 99% of the vaccinees, respectively, had concentrations greater than 0.15 micrograms/ml. After the third dose geometric mean concentrations increased to 13.7 micrograms/ml and all had concentrations greater than 0.15 micrograms/ml. The geometric mean Hib CPS antibody concentrations decreased to 1.24 micrograms/ml 18 months after the third injection, but 97% still had concentrations greater than 0.15 micrograms/ml. The rise of Hib CPS antibodies was mostly in the IgG class. The most pronounced increase was seen in the IgG1 subclass but there were also increase in IgG2 and IgG3. Protective concentrations of TT antibodies were found in all postimmunization sera. In conclusion Hib-TT is safe and immunogenic in infants and should be protective from 6 to 30 months and probably longer thereafter.     

Clinical and immunologic responses to the capsular polysaccharide of Haemophilus influenzae type b alone or conjugated to tetanus toxoid in 18- to 23-month-old children

The safety and immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) alone, or covalently bound to tetanus toxoid in saline solution (Hib-TT) or adsorbed onto AI(OH)3 (Hib-TT ads), were evaluated after one injection into 18- to 23-month-old healthy children in Sweden. No side reactions were elicited by Hib CPS; side reactions elicited by the two conjugates were similar and comparable to those reported for diphtheria and tetanus toxoids adsorbed. Hib-TT was the most immunogenic of the three vaccines, eliciting about 10-fold higher antibody levels than Hib CPS; of 28 vaccinees, all had greater than 1.0 microgram Ab/mL serum after immunization with Hib-TT. Increases of Hib CPS antibodies within immunoglobulin classes induced by the three vaccines were, in decreasing order, IgG greater than IgM greater than IgA. Within IgG subclasses, rises in IgG1 Hib CPS antibodies were the most frequent, followed by IgG2; some vaccinees with high postimmunization levels also had rises in IgG3 and one in IgG4. Immunization-induced Hib CPS antibodies were bactericidal. Hib-TT also elicited higher levels of tetanus toxoid antibodies than Hib-TT ads; these tetanus toxoid antibodies neutralized tetanus toxin in vivo.     

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.     

Diphtheria, tetanus and pertussis antibodies in 10-year-old children before and after a booster dose of three toxoids: implications for the timing of a booster dose

In an open study, 502 10-year-old children, who had received primary vaccination against diphtheria and tetanus in infancy and had varying histories of pertussis disease and vaccination, were vaccinated with diphtheria-tetanus vaccine (DT) alone or with the addition of 20 µg or 40 g of pertussis toxoid. Diphtheria toxin neutralising antibodies, pertussis toxin IgG and tetanus toxoid IgG antibodies were measured before and 1 month after the booster. All toxoids were highly immunogenic. In pertussis toxoid recipients, median levels of pertussis toxin IgG increased to 16.5 U/ml (DTaP20) and to 36 U/ml (DTaP40) in children with non-detectable (<1 U/ml) antibodies before vaccination and to >400 U/ml in children (both DTaP20 and DTaP40) with detectable antibodies before vaccination. A total of 60 children (12%) with non-detectable (<0.01 IU/ml) diphtheria antibodies and 36 children (7%) with non-detectable (<0.01 IU/ml) tetanus antibodies before the booster had lower median antibody concentrations post-vaccination than children with detectable antibodies before the booster (diphtheria: 5.12 vs. 20.48 IU/ml; tetanus: 4.0 vs. 10.0 IU/ml). There were no differences in diphtheria and tetanus antibodies after vaccination between children who did and did not receive pertussis toxoid. Conclusion:10-year-old children with non-detectable diphtheria and tetanus antibodies before the booster had lower post-vaccination antibodies than those with detectable antibodies before the booster indicating a poor immunological memory. Addition of pertussis toxoid to diphtheria-tetanus vaccine did not affect the antibody responses to diphtheria and tetanus toxoids when the three toxoids were combined as a booster. Even though immunity to diphtheria and tetanus was only estimated by surrogate markers (serum antitoxin antibodies) the results indicate that a lower age for the booster dose of diphtheria-tetanus vaccine or diphtheria-tetanus acellular pertussis vaccine should be considered.     

Reactogenicity and immunogenicity profiles of a novel pentavalent diphtheria-tetanus-whole cell pertussis-hepatitis B and Haemophilus influenzae type B vaccine: a randomized dose-ranging trial of the Hib tetanus-conjugate content

BACKGROUND: Combined vaccines containing diphtheria-tetanus-pertussis whole-cell (DTPw), Haemophilus influenzae type b (Hib), and hepatitis-B vaccines are essential for the continuing success of vaccination programs in developing nations. This randomized, dose-ranging study assessed the immunogenicity and reactogenicity of primary and booster vaccination with pentavalent DTPw-HBV/Hib vaccines containing 10, 5 or 2.5 microg of polyribosylribitol phosphate (PRP) conjugated to tetanus toxoid (trials Hib-052/064). METHODS: Six hundred eighty infants were randomized to receive one of 5 vaccine combinations at 6, 10, and 14 weeks of age. Of these, 351 received the same vaccine at 15-24 months of age. The immune response was evaluated on blood samples collected 1 month after the 3-dose primary course and before and 6 weeks after the booster dose. Reactogenicity was assessed during a 4-day period after each vaccine dose using diary cards. RESULTS: After primary vaccination, all subjects had seroprotective anti-PRP antibody concentrations (> or = 0.15 microg/mL) and > 95% had concentrations > or = 1.0 microg/mL, irrespective of the PRP dose administered. Anti-PRP antibody avidity after primary vaccination and antibody persistence until the second year of life were similar among groups. The booster dose induced marked increases in anti-PRP antibody GMCs and antibody avidity, indicative of effective priming and the presence of immune memory. All vaccination regimens elicited good immune responses and comparable antibody persistence to the other vaccine antigens, with significant increases in all antibody concentrations observed after boosting. All vaccination regimens were safe, with similar overall reactogenicity profiles. CONCLUSION: Hib conjugate vaccines containing reduced amounts of PRP can be effectively combined with the licensed DTPw-HBV vaccine to provide protection against 5 major childhood pathogens in a single injection.     

Antibody persistence and booster vaccination during the second and fifth years of life in a cohort of children who were born prematurely

BACKGROUND: These studies assessed the immunogenicity and reactogenicity of booster vaccination with diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-adsorbed conjugated Haemophilus influenzae type b (DTaP-HBV-IPV/Hib) at 18-20 months, and with DTaP during the fifth year of life in children who had been born prematurely (<37 weeks gestation). METHODS: Open-label, parallel group studies in which preterm and full-term subjects primed with DTaP-HBV-IPV/Hib received booster vaccination with DTaP-HBV-IPV/Hib (Infanrix hexa) at 18-20 months and DTaP (Infanrix) at 4 years of age. Immunogenicity was assessed before and 1 month after DTaP-HBV-IPV/Hib dose and 1 month after DTaP administration. Local and general symptoms were recorded for 4 days, unsolicited symptoms for 31 days after each dose. RESULTS: Before the second year booster, Hib, hepatitis-B, and polio type 3 seroprotection rates were higher in the full-term group (antipolyribosyl ribitol phosphate > or =0.15 microg/mL observed in 76.2%/83.6% preterm/full term respectively, anti-HBs > or =10 mIU/mL in 75.0%/80.6% respectively). One month after the DTaP-HBV-IPV/Hib booster, > or =98% in both groups were seroprotected/seropositive for all vaccine antigens, except hepatitis-B in preterms (seroprotection rate 91.6%). By the fifth year hepatitis-B seroprotection rates were 85.3%/70.5% (preterm/full term) in subjects who had previously responded to hepatitis-B vaccination, and seroprotection rates for polio and polyribosyl ribitol phosphate were >95%. No differences between groups were observed after the DTaP booster. Both booster doses were generally well tolerated with minimal differences observed between groups. Local symptoms occurred more frequently after the fifth vaccination at 4 years of age. CONCLUSIONS: Despite trends for lower immune responses to some vaccine antigens in preterm subjects, these findings support undelayed primary and booster vaccination in infants and children born before term. Booster vaccinations with DTaP-HBV-IPV/Hib and DTaP were well tolerated in this susceptible group.     

Haemophilus influenzae type b: the search for a vaccine

In adults Hib CPS protein conjugates are much more immunogenic than the polysaccharide alone; further studies have shown that they induce a booster response in children. The antibodies produced in response to the conjugates have the same biologic properties, isotype and IgG subclass composition as those elicited by Hib CPS alone or those present in serum after convalescence from Hib disease. More recently attempts have been made to make the conjugates compatible with DTP vaccine. In this procedure DTP is absorbed onto aluminum compounds (aluminum hydroxide or phosphate), with the effect of significantly prolonging diphtheria and tetanus antibody synthesis. Adsorption of the Hib CPS conjugate under controlled conditions does not alter the total amount of antibody elicited in infant rhesus monkeys after the third or final injection. The appearance of Hib CPS antibodies after the first injection, however, is accelerated with conjugate that has been adsorbed. This is an encouraging finding, because it means that more polysaccharide conjugates can be compatible with existing DTP vaccine.     

Haemophilus influenzae type b conjugate vaccine diluted tenfold in diphtheria-tetanus-whole cell pertussis vaccine: a randomized trial

BACKGROUND: Despite their proven efficacy Haemophilus influenzae type b (Hib) conjugate vaccines are not given to most children in the developing world in the face of an estimated global Hib disease burden of nearly 2 million cases per annum. A major barrier to the introduction of the vaccine would be overcome by diluting the vaccine 10-fold in diphtheria-tetanus-whole cell pertussis (DTP). We report a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib dose. METHODS: We randomized 168 infants to receive either the full dose Hib polysaccharide-tetanus toxoid conjugate (PRP-T) vaccine or a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial. Infants were vaccinated at 6, 10 and 14 weeks of age and received a full dose as a test of immunologic memory at 9 months of age. Sera were collected at each visit and at 1 week after the booster dose. Serum anti-capsular PRP antibody concentrations were measured by enzyme-linked immunosorbent assay. RESULTS: After the primary vaccination series, 95% of infants in the full dose arm and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of > or = 1.0 microg/ml. Infants receiving the diluted vaccine had significantly higher titers of anti-PRP antibody in response to the booster dose (151.36 microg/ml vs. 68.55 microg/ml, P = 0.009). CONCLUSIONS: The 1/10 dose of PRP-T was as immunogenic and safe as the full dose. The technique of diluting a single dose of PRP-T in a 10-dose DTP vial could potentially allow the widespread introduction of Hib vaccine in resource-poor countries currently unable to afford full dose Hib conjugate vaccine.     

Hepatitis A booster vaccine in children after infant immunization

BACKGROUND: Hepatitis A vaccine provides long term protection against hepatitis A infection in adults and children older than 2 years of age. Few data are available regarding children younger than 2 years of age. METHODS: Children who were vaccinated in infancy with hepatitis A vaccine were revaccinated at 4 years of age, and antibody titers were followed. Forty-four subjects who had been vaccinated with hepatitis A vaccine [Havrix, 360 enzyme-linked immunosorbent assay units (EU)] at the age of 2, 4 and 6 months were revaccinated with 720 EU of inactivated hepatitis A vaccine (Havrix) at 4 years of age. RESULTS: Geometric mean titer (GMT) of 44 evaluable cases was 41 mIU/ml and 34 children (77.3%) were seropositive before the booster dose. Postvaccination blood samples were obtained from 37 cases. One month after booster dose GMT increased to 2884 mIU/ml, and all subjects were seropositive. Ten seronegative cases also seroconverted. The GMT of the seropositive cases showed anamnestic response after the booster dose (57 mIU/ml before booster dose, 5623 mIU/ml after the booster). No serious adverse event was seen after the booster dose. CONCLUSION: We conclude that childhood hepatitis A virus revaccination after infant immunization is highly immunogenic and safe.     

Studies on Pneumococcus vaccine alone or mixed with DTP and on Pneumococcus type 6B and Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugates in two- to five-year-old children with sickle cell anemia

Pneumococcus vaccine, injected alone or mixed with diphtheria-tetanus toxoid-pertussis, did not elicit significant concentrations of pneumococcus type 6 antibodies in 2- to 5-year-old sickle cell anemia patients (n = 22). Reinjection 5 months later failed to elicit a booster response to pneumococcus type 6. We then injected conjugates of pneumococcus type 6B and of Haemophilus influenzae type b (Hib), each bound to tetanus toxoid (TT), alternatively at monthly intervals into sickle cell anemia patients of the same age group (n = 25); most received 3 injections of each vaccine. Pneumococcus vaccine was administered to 19 patients and Hib to 1 at approximately 1 year of age. Blood samples were taken before each and approximately 6 months after the last injection. Infrequent and minimal local reactions and only 6 episodes of fever (3%) occurred after injection of the conjugates. Pneumococcus type 6B-TT elicited a rise in the geometric mean concentration of pneumococcus type 6 antibodies (Ab) from 104 ng of antibody nitrogen (AbN)/ml in preimmunization sera to 385 ng of AbN/ml after the first injection (P less than 0.01). There were further increases after the 2 subsequent injections; 6 months after the third injection, the mean concentration was 940 ng of AbN/ml and 15 of 16 (94%) had greater than 300 ng of AbN/ml. Hib-TT elicited a 160-fold increase of Hib antibodies to a geometric mean concentration of 39.0 micrograms of Ab/ml after the first injection. These levels rose approximately 2-fold following 2 additional injections to 71.7 micrograms/ml and declined to 10.7 micrograms/ml at the 6-month sampling.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long term antibody response to hepatitis B vaccination beginning at birth and to subsequent booster vaccination

BACKGROUND: Few studies have examined the long term persistence of antibody after hepatitis B immunization beginning at birth and the response to a subsequent challenge with a booster dose of vaccine. METHODS: Two groups of children received hepatitis B vaccine on a schedule of birth and 1 and 6 months of age. Group 1 received recombinant vaccine and a booster dose at 5 years of age. Group 2 received plasma-derived vaccine and a booster dose at 9 years of age. Group 1 children were tested for antibody after the primary vaccine series. All children were tested for antibody before administration of the booster dose and at 2 and 4 weeks and 1 year after the booster. In addition all children were tested for markers of hepatitis B virus infection. RESULTS: Antibody testing conducted after the primary series for children in Group 1 (n = 70) showed that 90% had protective antibody concentrations at 13 months of age, and testing before the booster dose showed that 41% had protective antibody concentrations. All children with protective antibody concentrations after the primary series had an anamnestic antibody response to the booster dose. In Group 2 (n = 41) 39% of children had protective antibody concentrations before the booster dose, and 93% had an anamnestic antibody response to the booster dose. One year after the booster dose there were 26-fold and 11-fold declines in antibody concentration in Groups 1 and 2, respectively. CONCLUSIONS: A primary vaccination series with either plasma-derived or recombinant hepatitis B vaccine affords long term protection for children when vaccinated beginning soon after birth.     

Immunogenicity and safety of a pneumococcal conjugate 7-valent vaccine in infants with sickle cell disease

OBJECTIVES: To evaluate safety and immunogenicity of the pneumococcal 7-valent conjugate vaccine (PCV7) when administered to infants with sickle cell disease (SCD) at 2, 3, and 4 months of age with a booster dose of a 23-valent pneumococcal polysaccharide vaccine (PS-23) at 15 to 18 months of age. METHODS: This open-label multicenter study in France enrolled 2-month-old infants with SCD. Blood samples for the determination of antibody concentrations to vaccine serotypes were obtained immediately before and 1 month after the primary immunization, and before and 1 month after the PS-23 booster. Local and systemic reactions were recorded on diary cards. RESULTS: Of the 51 infants enrolled, 49 received primary immunization and 46 received the booster dose. After primary immunization > or =95% of the subjects had antibody titers > or =0.35 microg/mL for the 7 serotypes. After boosting, geometric mean concentrations were high for all serotypes, ranging from 6.32 microg/mL (serotype 18C) to 29.49 microg/mL (serotype 4). Except for 1 case after administration of the booster dose, all fevers reported were less than 39 degrees C. No vaccine-related serious adverse events were reported. CONCLUSIONS: PCV7 administered at 2, 3, and 4 months of age in infants with SCD was well-tolerated, highly immunogenic, and primed for immune memory as indicated by the dramatic response to the PS-23 dose administered at 15-18 months in this study. However, the current recommended schedule is to boost with the PCV7 at 12-15 months of age and for these high-risk children, to enlarge the protection with a subsequent PS-23 dose at 2 years of age.     

The majority of children and adolescents with acute myeloid leukemia have detectable anti-DT388-GMCSF IgG concentrations,but at concentrations that should not preclude in vivo activity

PURPOSE: As a novel approach for the treatment of acute myeloid leukemia (AML), the authors are developing a fusion toxin (DT(388)-GMCSF) consisting of a truncated diphtheria toxin (DT(388)) linked to human granulocyte-macrophage colony-stimulating factor (GMCSF). A critical step in the development of DT(388)-GMCSF for clinical use in childhood and adolescent AML is to determine whether children and adolescents have preexisting antibodies to DT(388)-GMCSF due to childhood immunizations against diphtheria toxoid. PATIENTS AND METHODS: Sera from 33 children and adolescents with AML and one with juvenile myelomonocytic leukemia were collected. The median age was 11.8 years. All scheduled diphtheria toxoid vaccinations were current except for the child diagnosed at 4 months of age. Anti-DT(388)-GMCSF antibody concentrations were detected by an enzymoimmunoassay and by an in vitro bioassay. RESULTS: Thirty of 34 (88%) children and adolescents had detectable anti-DT(388)-GMCSF IgG antibody concentrations. The median concentration was 1.5 microg/mL, with a range from undetectable to 191.4 microg/mL. There was a positive correlation between the enzymoimmunoassay and bioassay. There was no difference between the anti-DT(388)-GMCSF IgG concentrations in these children and adolescents with AML and in 43 adults with AML. Preliminary results of the phase 1 trial of DT -GMCSF in adults with AML indicate that patients with baseline anti-DT(388)-GMCSF IgG concentrations of less than 2 microg/mL can achieve circulating DT(388)-GMCSF concentrations and can exhibit antileukemic activity. Twenty-three of 34 (67.6%) children and adolescents had anti-DT(388)-GMCSF IgG concentrations less than 2 microg/mL. CONCLUSIONS: Despite routine diphtheria toxoid vaccinations, most children and adolescents with AML do not have anti-DT -GMCSF IgG concentrations that preclude in vivo activity of DT -GMCSF.     

Long term enhancement of the IgG2 antibody response to Haemophilus influenzae type b by breast-feeding

SUBJECTS: Sets of sera were obtained from 30 children <6 years of age with invasive type b (Hib) infection and their mothers. Duration and mode of breast-feeding were monitored. Titers of IgG1, IgG2, IgA and IgM antibodies against Hib capsular polysaccharide were determined in sera taken during the acute illness and during early and late convalescence. RESULTS: Children 18 months or older with longer durations of exclusive breast-feeding (13 weeks or more; mean, 19.3 weeks) had higher Hib antibody concentrations of the IgG1, IgG2, IgA and IgM isotypes than those with a shorter duration of exclusive breast-feeding (<13 weeks; mean, 5.4 weeks). The difference was greatest for the IgG2 isotype. In regression analyses the association between the duration of exclusive breast-feeding and the anti-Hib IgG2 concentration was significant when breast-feeding, type of Hib infection, maternal Hib antibody titer and age were used as explanatory factors. In the group of 14 children <18 months of age no significant differences were noted. DISCUSSION: This study indicates the presence of a long lasting enhancing effect of breast-feeding on the antibody response to Hib in children, in particular on IgG2 Hib antibody production. This may result from the content in the milk of IFN-gamma and IFN-gamma-producing cells and possibly other factors, which can support IgG2 antibody production.     

Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease

Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001), concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.     

Immunogenicity and reactogenicity of a Haemophilus influenzae type b tetanus conjugate vaccine when administered separately or mixed with concomitant diphtheria-tetanus-toxoid and acellular pertussis vaccine for primary and for booster immunizations

With an increasing number of new vaccines available for routine childhood immunization, combination vaccines are needed in order to maintain or achieve a high compliance with recommended immunization programmes. In a prospective, randomized, comparative, multi-centre study, 822 healthy infants were enrolled to receive three doses of either a candidate or a commercially available Haemophilus influenzae type b (Hib) vaccine concomitantly with diphtheria-, tetanus- acellular pertussis (DTaP) vaccine. Study subjects were randomly allocated to one of the following groups: (1) separate, or (2) mixed injection of DTaP and candidate Hib vaccine, or (3) separate injection of DTaP and commercial Hib vaccine. One year later the first 189 study subjects received either separate or mixed injections of the same Hib and DTaP vaccines as booster doses. Evaluation of reactogenicity was based on diary cards completed by parents. Immunogenicity was documented by measuring IgG antibody concentrations in serum samples taken before and 4 weeks after primary and booster vaccination. No serious adverse events occurred and most local and systemic reactions were mild to moderate. Booster doses were more reactogenic than primary doses with all groups. Antibody concentrations against pertussis antigens were similar to those seen with DTaP alone. All but one subject had protective antibody concentrations against diphtheria and tetanus. Primary immune response to the Hib vaccine was significantly lower in the group receiving the mixed Hib-DTaP vaccine, however, ≥95% of vaccinees had anti-Hib antibody concentrations ≥0.15 μg/ml and there was a marked booster response (>100-fold) in all groups. Conclusions Mixing DTaP and Hib vaccines for primary immunization caused a decrease in anti-Hib antibody response, although after primary immunization as after booster doses, all subjects showed antibody concentrations considered to be protective for invasive Hib disease. Mixing of the vaccines did not result in increased reactogenicity. Received: 13 June 1997 / Accepted in revised form: 4 September 1997     

Fifth vaccination with dipthteria, tetanus and acellular pertussis is beneficial in four- to six-year-olds

OBJECTIVE: Diphtheria, tetanus and pertussis serum antibody titers were assessed before a fifth dose of diphtheria-tetanus-acellular pertussis (DTaP) or diphtheria-tetanus-whole cell pertussis (DTwP) vaccination at age 4 to 6 years. METHODS: Healthy children who had participated in a series of National Institutes of Health-sponsored trials assessing DTwP and DTaP vaccines provided prevaccination sera before a fifth dose of DTwP or DTaP. The trial design was prospective, randomized and double blind. Diphtheria, tetanus and pertussis antibody titers were measured by enzyme-linked immunosorbent assay. Pertussis results are expressed in enzyme-linked immunosorbent assay units/ml based on US Food and Drug Administration reference sera. Tetanus and diphtheria toxin concentrations are expressed in IU/ml with a WHO international reference sera as a standard. RESULTS: For diphtheria 100% of the children had antibody titers above the minimum protective level of 0.01 IU/ml and 86 to 100% (depending on prior vaccine product) had titers >0.1 IU/ml. However, only 0 to 40% of the children had antibody titers > or =1.0 IU/ml, a titer associated with more certain durable protection. For tetanus none of the children had an antibody titer below 0.01 IU/ml, and 93 to 100% had titers > or =0.1 IU/ml, a titer associated with more certain, durable protection. For pertussis the geometric mean concentrations of antibody before booster were uniformly very low, and the percentage of children exceeding the minimum detectable titer of antibody by 4-fold was also low. CONCLUSION: Before a 4- to 6-year-old booster, a large proportion of children have titers of antibody to diphtheria below the certain, durable protective level. Because serologic correlates and minimum protective titers of antibody to pertussis antigens have not been established, the relevance of the low titers determined in the current study is unknown but a potential concern.     

Immunoglobulin E and G antibodies two years after a booster dose of an aluminium-adsorbed or a fluid DT vaccine in relation to atopy

Iinnumoglobi. il in E and G levels lo diphtheria and tetanus toxoids were investigated two years after a DT booster wilh either an adsorbed or a nonadsorbed, fluid vaccine, given at 10 years of age. Although IgE levels had declined, detectable IgE to diphtheria and tetanus toxoids were still found in 82% and 67% of samples, respectively, to be compared to prebooster levels of 3-14% and postbooster levels of 92-94%. The IgG levels had also declined hut remained at equal and high levels in both the adsorbed and the fluid vaccine groups. The prevalence of allergic symptoms was similar in the two vaccination groups. Thus, the study showed an unexpected, long duration of the IgE responses elicited by a booster dose of DT vaccine. The booster dose also induced a durable, high IgG antibody response to both the adsorbed and the fluid vaccine.     

Immunogenicity and safety of a DTaP-IPV//PRP～T vaccine (Pentaxim) booster dose during the second year of life in Indian children primed with the same vaccine

Objective

To evaluate the immunogenicity and safety of a pentavalent (diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Hib polysaccharide-conjugate) combination vaccine booster dose.

Design

Multicenter, open, Phase III clinical study.

Setting

Two tertiary-care hospitals in Delhi and Vellore, India.

Participants/patients

207 healthy Indian children.

Intervention

The DTaP-IPV//PR～NT vaccine (Pentaxim) was given at 18–19 months of age to children who had been primed with the same vaccine at 6,10,14 weeks of age.

Main outcome measures

Immunogenicity was assessed before and 1 month after the booster. Safety was evaluated from parental reports, and investigator assessments.

Results

At 18–19 months of age, before boosting, the SP rates against diphtheria, tetanus, poliovirus and PRP were 82.3–100%; 90.0% of participants had anti-PRP ≥0.15 μg/mL. Anti-poliovirus titers were ≥1:8 dilution in 97.9–98.4% of participants. Anti-PT and FHA titers ≥5 EU/mL) were detectable in 82.5% and 90.8% of participants, respectively. One month after the booster dose, SP rates were 99.5% for PRP (≥1.0 μg/mL), 100% for diphtheria, tetanus (≥0.1 IU/mL) and polioviruses (≥8:1/dilution). Seroconversion (4 fold post-booster increase in anti-PT and -FHA concentration) occurred in 96.8% and 91.7%, respectively. Geometric mean concentrations (GMC) increased from 11.7 to 353.1 EU/mL and from 18.2 to 363.4 EU/mL for anti-PT and anti-FHA, respectively. Anti-PRP GMC increased from 1.75 to 70.5 μg/mL. Vaccine reactogenicity was low; severe solicited reactions were reported by <1.4% of participants.

Conclusion

The DTaP-IPV//PRP-T vaccine booster at 18–19 months of age was well tolerated and induced strong antibody responses.     

Immunogenicity and reactogenicity of DTPa-HBV-IPV/Hib vaccine as primary and booster vaccination in low-birth-weight premature infants

AIM: To assess suitability of a combined DTPa-HBV-IPV/Hib vaccine (Infanrix hexa) for immunization of low-birth-weight (<2.0 kg) preterm infants, with particular focus on the hepatitis B response. METHODS: Open-label study in 170 preterm infants receiving primary vaccination at 2, 4 and 6 months of age and booster vaccination at 18-24 months. Enrollment and analysis were stratified in two groups: infants with birth weight between 1.5 kg and 2.0 kg (low birth weight: LBW), infants with BW <1.5 kg (very low birth weight: VLBW). RESULTS: One month after the three dose primary vaccination, 93.7% and 94.9% of infants in VLBW and LBW groups, respectively, had anti-HBs antibody concentrations > or = 10 mIU/mL. High seroprotection and response rates (92.4-100%) to all vaccine antigens were observed. Those were reinforced (>98%) by booster vaccination for all antigens except for HBs in VLBW children: only 88.7% of those had anti-HBs antibody concentrations > or = 10 mIU/mL, compared with 96.5% of LBW children (difference statistically not significant). The vaccine was well tolerated in both groups of infants. CONCLUSION: Preterm infants will benefit by the administration of a primary and booster vaccination with DTPa-HBV-IPV/Hib vaccine.