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 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.     

Antibodies against Haemophilus influenzae type b capsular polysaccharide and tetanus toxoid before and after a booster dose of the carrier protein nine years after primary vaccination with a protein conjugate vaccine

IgG antibodies against Haemophilus influenzae type b (Hib) capsular polysaccharide (CPS) and tetanus toxoid (TT) were measured for 53 children, 10 years of age, before and 1 month after a booster dose of diphtheria-tetanus vaccine (DT). All children had been vaccinated at 3, 5 and 12 months of age with DT and a Hib-TT conjugate. Geometric mean concentrations of Hib CPS serum IgG antibody were 4.16 and 4.30 microg/mL before and after the DT booster, respectively. The geometric mean concentration of TT IgG antibody increased from 0.09 IU/mL to 4.58 IU/mL (P < 0.001). Hib CPS IgG levels remained well above protective titers for 9 years after 3 doses of Hib-TT appropriately spaced in infancy. A booster dose of TT did not affect Hib CPS antibody concentrations but induced a pronounced IgG response against TT.     

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.     

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)     

Isotype composition of antibodies to streptococcus group B type III polysaccharide and to tetanus toxoid in maternal,cord blood sera and in breast milk

Neonates are protected against group B streptococcal (GBS) infections and tetanus by transplacentally transferred serum antibodies. Antibodies of the immunoglobulin (Ig) G, IgM and IgA classes and IgG subclasses to the capsular polysaccharide (CPS) of type III group B streptococci (GBS III) and to tetanus toxoid (TT) were measured in sera from healthy women of fertile age and in paired maternal and cord blood sera from term and preterm pregnancies. GBS III CPS antibodies of the IgG class were found in sera from 97 out of 100 women of fertile age, but only 15 of them had antibodies above the proposed protective level (2 g/ml). TT IgG antibodies above the protective level (0.01 units/ml) were found in all sera. The IgG antibodies against GBS III CPS were mainly composed of the IgG2 subclass and to a lesser extent of IgG1. Almost all women had IgG1 antibodies against TT and 40% had IgG4 antibodies. Total IgG and IgG1 antibodies against GBS III CPS were higher in cord blood sera from 37 term neonates than in sera from their mothers whereas IgG2 antibody levels were similar. Total IgG and IgG1 antibodies against TT were also higher in the 20 term neonates tested than in their mothers. In contrast, total IgG and IgG1 to both GBS III CPS and TT and IgG2 to GBS III CPS were lower in cord blood sera from preterm neonates than in sera from their mothers. IgA antibodies to GBS III CPS were detected in 63% of breast milk samples while IgA antibodies against TT were detected in only 4%. In conclusion the study shows important differences in IgG subclass composition of antibodies against a polysaccharide and a protein antigen and in placental transfer of IgG antibodies in term and preterm babies.     

Immunogenicity of Haemophilus influenzae type b conjugate vaccines in infant rhesus monkeys

Two Haemophilus influenzae type b (Hib) polysaccharide-protein conjugate vaccines were evaluated for immunogenicity in eliciting anti-polyribosyl ribitol phosphate (PRP) antibodies in infant rhesus monkeys. Animals received intramuscular injections of either Hib polysaccharide (PRP)-meningococcal outer membrane protein complex or Hib oligosaccharide-CRM197 (HbOC) conjugate vaccines on d 0, 28, and 56. Because HbOC contains the CRM197 mutant diphtheria toxin from Corynebacterium diphtheriae as its protein carrier, the effect of simultaneous injection of diphtheria toxoid on the immunogenicity of HbOC also was evaluated by dividing monkeys vaccinated with HbOC into three groups: HbOC/saline, HbOC/diphtheria and tetanus toxoids, and HbOC/tetanus toxoid (coadministration of HbOC and other vaccine or placebo injected into the flank muscle of different legs). Infant monkeys vaccinated with the PRP-outer membrane protein complex conjugate responded with anti-PRP antibody after the first dose and showed booster responses after the second and third injections. In contrast, infant monkeys vaccinated with HbOC did not respond after three doses of HbOC/saline or HbOC/tetanus toxoid. However, two of three monkeys given concurrent injections of HbOC and diphtheria and tetanus toxoids did respond. The nonresponder monkey to three doses of HbOC and diphtheria and tetanus toxoids did respond to a subsequent injection with PRP-outer membrane protein complex. Thus, concomitant administration of diphtheria toxoid, a common vaccine for human infants, is necessary to elicit an anti-PRP antibody response to HbOC.(ABSTRACT TRUNCATED AT 250 WORDS)     

DT5aP-Hib-IPV and MCC vaccines: preterm infants' response to accelerated immunisation

Aims: To describe the immune response of preterm infants to combined diphtheria/tetanus/5 component acellular pertussis-Haemophilus influenzae type b inactivated polio vaccine (DT5aP-Hib-IPV) and meningococcal serogroup C conjugate vaccine (MCC) under accelerated schedule. To compare results with term infants immunised with DT5aP-Hib-IPV and with historical data from preterm infants immunised with a DT3 component aP-Hib vaccine. Methods: Prospective observational study in preterm infants born at <32 weeks gestation with comparison to contemporary cohort of term infants. DT5aP-Hib-IPV and MCC vaccines were given at 2, 3, and 4 months. Results: Fifty preterm infants (mean gestational age 28.5 weeks) completed the study. After three doses of vaccines Hib polysaccharide IgG geometric mean concentration (GMC) was 1.21 µg/ml with 80% ⩾0.15 µg/ml; MCC serum bactericidal assay geometric mean titre (GMT) was 1245 with 100% ⩾8. All infants achieved protective titres to diphtheria, tetanus, and the three poliovirus types with ⩾80% achieving protective rises in IgG against the five pertussis antigens. Conclusion: Preterm infants immunised with DT5aP-Hib-IPV and MCC vaccines show IgG responses to Hib and MCC greater than seen historically in both term and preterm infants with a DT3aP-Hib vaccine, and for pertussis antigens and poliovirus type 1 responses similar to that seen in term infants immunised with DT5aP-Hib-IPV. Responses to poliovirus types 2 and 3 are reduced, but all infants achieved protective titres.     

Antibody Responses to Parenteral and Oral Vaccines Are Impaired by Conventional and Low Protein Formulas as Compared to Breast-feeding

ABSTRACT. The vaccine response to poliovirus, diphtheria and tetanus toxoids in relation to protein intake was studied in infants, either breast-fed or given low (1.1 g/100 ml) or conventional (1.5 g/100 ml) protein formula. Serum, salivá and faeces antibodies were measured by the enzyme-linked immunosorbent assay. Neutralizing poliovirus antibodies were determined. The serum, saliva and faeces antibody responses in the two formula-fed groups of infants did not differ significantly, but for the low protein formula group which had significantly higher serum neutralizing titres to poliovirus after the second vaccine dose than the conventional formula group. However, the breast-fed group had significantly higher antibody levels than the two formula-fed groups together: serum IgG to diphtheria toxoid (p<0.01) and serum neutralization of poliovirus (p<0.001) at 21-40 months of age, saliva secretory IgA to tetanus (p<0.01), diphtheria toxoid (p<0.01) and poliovirus (p<0.05), as well as faecal IgM to tetanus toxoid (p<0.05) and poliovirus (p <0.01 and p <0.05) at 3 and 4 months of age. Breast-fed infants thus showed better serum and secretory responses to peroral and parenteral vaccines than the formula-fed, whether with a conventional or low protein content.     

DT5aP-Hib-IPV and MCC vaccines: preterm infants' response to accelerated immunisation.

AIMS: To describe the immune response of preterm infants to combined diphtheria/tetanus/5 component acellular pertussis-Haemophilus influenzae type b inactivated polio vaccine (DT5aP-Hib-IPV) and meningococcal serogroup C conjugate vaccine (MCC) under accelerated schedule. To compare results with term infants immunised with DT5aP-Hib-IPV and with historical data from preterm infants immunised with a DT3 component aP-Hib vaccine. METHODS: Prospective observational study in preterm infants born at <32 weeks gestation with comparison to contemporary cohort of term infants. DT5aP-Hib-IPV and MCC vaccines were given at 2, 3, and 4 months. RESULTS: Fifty preterm infants (mean gestational age 28.5 weeks) completed the study. After three doses of vaccines Hib polysaccharide IgG geometric mean concentration (GMC) was 1.21 microg/ml with 80% > or =0.15 microg/ml; MCC serum bactericidal assay geometric mean titre (GMT) was 1245 with 100% > or =8. All infants achieved protective titres to diphtheria, tetanus, and the three poliovirus types with > or =80% achieving protective rises in IgG against the five pertussis antigens. CONCLUSION: Preterm infants immunised with DT5aP-Hib-IPV and MCC vaccines show IgG responses to Hib and MCC greater than seen historically in both term and preterm infants with a DT3aP-Hib vaccine, and for pertussis antigens and poliovirus type 1 responses similar to that seen in term infants immunised with DT5aP-Hib-IPV. Responses to poliovirus types 2 and 3 are reduced, but all infants achieved protective titres.     

Subnormal serum concentrations of IgG2 in children with frequent infections associated with varied patterns of immunologic dysfunction

To characterize more fully the immunologic basis for increased susceptibility to infection in patients with low serum concentrations of IgG2, we identified eight infection-prone children, 1 to 2 years of age, with serum IgG2 concentrations greater than 2 SD below the mean for age and followed their serologic and clinical courses for 1 to 3 years. Two of the eight children became clinically and immunologically normal and may have had transient IgG2 deficiency with an exaggerated developmental delay of this late-maturing subclass. The remaining six subjects had persistently subnormal or low-normal serum IgG2 levels and continued to experience frequent infections. All six of these children responded poorly to Haemophilus influenzae type b (Hib) polysaccharide, and four of six responded poorly to Streptococcus pneumoniae type 3 polysaccharide. Both IgG1 and IgG2-specific antibody responses to these vaccines were abnormal. Three of these six children also responded poorly to tetanus toxoid, an antigen that normally induces a predominant IgG1 response. Although five of these six children produced antibodies in response to Hib polysaccharide protein conjugate vaccine, three of four given Hib oligosaccharide CRM conjugate vaccine required booster doses to respond, a pattern of response characteristic of infants less than 6 months of age. Further, although serum concentrations of IgG1 were normal, peripheral blood mononuclear cells from four of six children tested produced extremely small amounts of IgG1 and IgG3 as well as IgG2. Finally, varied patterns of abnormalities of IgG, IgA, IgM, and IgG4 became apparent in five of the six children with persistently low serum IgG2 values. This study demonstrates that subnormal serum concentrations of IgG2 may be associated with varied patterns of immunologic dysfunction, some of which are evolving and may be responsible for increased susceptibility of these children to infection.     

Avidity of tetanus and Hib antibodies after childhood acute lymphoblastic leukaemia - implications for vaccination strategies

AIM: To investigate the possible relationship between serum levels and avidities of antibodies against tetanus toxoid (TT) and Haemophilus influenzae type b (Hib) in children that were vaccinated after treatment for childhood acute lymphoblastic leukaemia (ALL). METHODS: The study groups were 31 paediatric patients with ALL and 18 healthy controls. All subjects were vaccinated with TT and a protein conjugated Hib vaccine. Antibody levels were analysed at three time points: At diagnosis of ALL, after cessation of treatment before vaccination and three weeks after vaccination. Avidity was measured twice, with a thiocyanate elution assay, at diagnosis of ALL and three weeks after vaccination. RESULTS: There was a correlation between level and avidity of tetanus antibodies after vaccination (r(s) = 0.59, P < 0.001). In the standard-risk and intermediate-risk ALL groups, all patients responded with protective levels of tetanus antibodies with normal avidity. In the high-risk ALL group 7/9 patients had subprotective levels of tetanus antibodies after vaccination and concomitantly the lowest avidity, implying poor protection against tetanus. No patients were found with low levels and low avidity of anti-Hib IgG, and 29/31 patients had full protection after a single dose of conjugated Hib-vaccine. CONCLUSION: The vaccination strategy after childhood ALL must be different for low-risk and high-risk ALL groups, since the high-risk group fail to elicit a recall response to tetanus.     

Immunogenicity and safety of a pertussis vaccine composed of pertussis toxin inactivated by hydrogen peroxide, in 18- to 23-month-old children

A new pertussis vaccine, composed of purified pertussis toxin inactivated by hydrogen peroxide and adsorbed onto aluminum hydroxide (NICHD-Ptxd), was injected into 60 children aged 18 to 23 months without a history of pertussis or pertussis vaccination. Two doses of toxoid, 10 and 50 micrograms, were used. Two injections, given 8 to 12 weeks apart, elicited increases in serum levels of antitoxin and IgG antibodies in 56 children who had no detectable antitoxin (less than 5 units) before vaccination. Four children with detectable antitoxin (greater than or equal to 5 units) before the first vaccination had pronounced antibody increases after the first dose. After the second dose, the geometric mean antitoxin concentration was 29 units with the 50 micrograms dosage and 10 units with the 10 micrograms dosage (p less than 0.001). Serum antibody levels elicited by two injections of 50 micrograms were similar to those in patients convalescing from pertussis. A third injection given to seven children 9 to 10 months after the second injection gave a booster response, with high levels of antitoxin (160 to 1280 units) and of IgG antibodies. With few exceptions the antibody response was restricted to the IgG class. Transient local reactions greater than or equal to 2 cm in diameter occurred in 14% of the children after the first dose and in 44% after the second and third doses. Moderate fever was recorded after 6% of all injections. There were no changes in peripheral blood leukocyte counts or fasting blood glucose levels measured before and 24 hours after the first injection. We conclude that NICHD-Ptxd is immunogenic in children. No serious adverse effects were noted.     

Antibody responses to parenteral and oral vaccines are impaired by conventional and low protein formulas as compared to breast-feeding

The vaccine response to poliovirus, diphtheria and tetanus toxoids in relation to protein intake was studied in infants, either breast-fed or given low (1.1 g/100 ml) or conventional (1.5 g/100 ml) protein formula. Serum, saliva and faeces antibodies were measured by the enzyme-linked immunosorbent assay. Neutralizing poliovirus antibodies were determined. The serum, saliva and faeces antibody responses in the two formula-fed groups of infants did not differ significantly, but for the low protein formula group which had significantly higher serum neutralizing titres to poliovirus after the second vaccine dose than the conventional formula group. However, the breast-fed group had significantly higher antibody levels than the two formula-fed groups together: serum IgG to diphtheria toxoid (p less than 0.01) and serum neutralization of poliovirus (p less than 0.001) at 21-40 months of age, saliva secretory IgA to tetanus (p less than 0.01), diphtheria toxoid (p less than 0.01) and poliovirus (p less than 0.05), as well as faecal IgM to tetanus toxoid (p less than 0.05) and poliovirus (p less than 0.01 and p less than 0.05) at 3 and 4 months of age. Breast-fed infants thus showed better serum and secretory responses to peroral and parenteral vaccines than the formula-fed, whether with a conventional or low protein content.     

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     

Effect of probiotics on vaccine antibody responses in infancy – a randomized placebo-controlled double-blind trial

Probiotics are immunomodulatory and may thus affect vaccine antibody responses. With the accumulating evidence of their health-promoting effects, probiotics are increasingly administered in allergy-prone infants. Therefore, we studied the effect of probiotics on antibody responses to diphtheria, tetanus and Haemophilus influenzae type b (Hib) vaccines in 6-month-old infants participating in a randomized placebo-controlled double-blind allergy-prevention trial. Mothers of unborn children at increased risk for atopy used a combination of four probiotic strains, or a placebo, for 4 wk before delivery. During 6 months from birth, their infants received the same probiotics and galacto-oligosaccharides, or a placebo. The infants were immunized with a DTwP (diphtheria, tetanus and whole cell pertussis) at ages 3, 4, and 5 months, and with a Hib polysaccharide conjugate at 4 months. Serum diphtheria, tetanus, and Hib IgG antibodies were measured at 6 months. In the probiotic group, protective Hib antibody concentrations (>/=1 microg/ml) occurred more frequently, 16 of 32 (50%) vs. six of 29 (21%) (p = 0.020), and the geometric mean (inter-quartile range) Hib IgG concentration tended to be higher 0.75 (0.15-2.71) microg/ml than in the placebo group 0.40 (0.15-0.92) microg/ml (p = 0.064). In these respective groups, diphtheria, 0.38 (0.14-0.78) vs. 0.47 (0.19-1.40) IU/ml (p = 0.449), and tetanus, 1.01(0.47-1.49) vs. 0.81 (0.56-1.39) IU/ml (p = 0.310), IgG titers were comparable. In conclusion, in allergy-prone infants probiotics seem not to impair antibody responses to diphtheria, tetanus, or Hib, but may improve response to Hib immunization.     

Combined diphtheria, tetanus, pertussis, and Haemophilus influenzae type b vaccines for primary immunisation

A total of 146 infants were immunised at ages 2, 3, and 4 months with a combined diphtheria, tetanus, pertussis (DTP)--Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) vaccine (Pasteur Merieux) to assess the antibody response and adverse events associated with immunisation. Adverse events, including fever, were recorded by parents in a diary for three days following each injection. Blood was taken before the first immunisation and four weeks after the third immunisation to assess antibody response. Data were compared with those from historical controls who had received DTP and PRP-T vaccines by separate injection. The combined vaccine was well tolerated. Rates of local and general reactions were similar to those reported for infants immunised by separate injection. All infants achieved protective antibody titres (> 0.01 IU/ml) for diphtheria and tetanus; 98% acquired Hib (PRP) antibody > 0.15 microgram/ml and 82.5% > 1.0 microgram/ml. Pertussis antibody titres (pertussis toxin, filamentous haemagglutinin, total agglutinins, and agglutinins 2 and 3) showed appreciable rise following immunisation. DTP and PRP-T vaccines provide similar antibody responses and adverse effects whether mixed in the same syringe or administered by separate injection. The vaccines could be combined for use in the United Kingdom primary immunisation schedule.     

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.     

Combined diphtheria,tetanus, pertussis,and Haemophilus influenzae type b vaccines for primary immunisation.

A total of 146 infants were immunised at ages 2, 3, and 4 months with a combined diphtheria, tetanus, pertussis (DTP)--Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) vaccine (Pasteur Merieux) to assess the antibody response and adverse events associated with immunisation. Adverse events, including fever, were recorded by parents in a diary for three days following each injection. Blood was taken before the first immunisation and four weeks after the third immunisation to assess antibody response. Data were compared with those from historical controls who had received DTP and PRP-T vaccines by separate injection. The combined vaccine was well tolerated. Rates of local and general reactions were similar to those reported for infants immunised by separate injection. All infants achieved protective antibody titres (> 0.01 IU/ml) for diphtheria and tetanus; 98% acquired Hib (PRP) antibody > 0.15 microgram/ml and 82.5% > 1.0 microgram/ml. Pertussis antibody titres (pertussis toxin, filamentous haemagglutinin, total agglutinins, and agglutinins 2 and 3) showed appreciable rise following immunisation. DTP and PRP-T vaccines provide similar antibody responses and adverse effects whether mixed in the same syringe or administered by separate injection. The vaccines could be combined for use in the United Kingdom primary immunisation schedule.     

Intensive treatment for childhood acute lymphoblastic leukemia reduces immune responses to diphtheria, tetanus, and Haemophilus influenzae type b

OBJECTIVES: Immunity to diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus influenzae type b (Hib) is affected in children with acute lymphoblastic leukemia (ALL). The aims were to examine immunity and to compare the response to immunization at 1 or 6 months after treatment. METHODS: Thirty-one patients were immunized with DT and conjugated Hib vaccine (ActHib) at 1 month or 6 months after treatment of ALL with the NOPHO 92 protocol. Antibody levels were determined before and 3 weeks after vaccination. Specific T and Hib antibody-secreting cells of IgG/IgA/IgM isotypes were analyzed in peripheral blood using an ELISPOT technique. RESULTS: All specific antibody levels decreased during ALL treatment, and protective levels after treatment were noted for 17% against D, 33% against T, and 100% against Hib. No high-risk patient had full D or T protection after treatment. After vaccination all the standard- and intermediate-risk patients achieved full protection against D, T, and Hib. The high-risk group showed insufficient immune response (full protection after vaccination: D 56%, T 22%, Hib 78%). No difference was found between vaccination at 1 month or 6 months after treatment. The poor antibody production in the high-risk group correlated to low numbers of antibody-secreting cells. CONCLUSIONS: Nonprotective antibody levels against D, T, and Hib after childhood ALL are more common than previously thought. Insufficient immune response was restricted to the high-risk group and was related to a low number of memory B cells in this study. Immunizations should be included in follow-up after childhood ALL, and the policy should be adapted to treatment intensity.