Joel S. Samuelson

Efficacy of haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy

Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine has recently been shown to be capable of inducing antibodies to H. influenzae in infants. In an evaluation of its clinical efficacy, 60,000 children were enrolled in an open trial in Finland. Children born on odd-numbered days between October 1, 1985, and September 30, 1986, received the vaccine at 3, 4, 6, and 14 months; those born on even-numbered days served as controls. The geometric mean antibody titer measured in a cohort of 99 children rose from a prevaccination level of 0.08 microgram per milliliter at three months of age to 0.42 microgram per milliliter at seven months. Only minor adverse reactions were reported. Up to February 1987, two cases of invasive H. influenzae infection had occurred among the children who had received three doses of vaccine, whereas 12 cases had occurred among the controls (P = 0.0005 by Poisson one-tailed test). The rate of short-term (average follow-up time, five months) protection provided by this conjugate vaccine in infancy was thus 83 percent.

Response of preterm infants to diphtheria-tetanus-pertussis immunizations*

To establish guidelines for the routine use of diphtheria, tetanus, and pertussis (DTP) vaccine in preterm infants, we quantitated antibody responses of preterm infants to DTP and determined the nature and extent of side effects. Twenty-five preterm infants were immunized with 0.5 ml DTP vaccine at routine intervals. Term infants served as controls. Immediately before each immunization and 2 months after the third, DTP-specific antibodies were quantitated. Clinical side effects were determined by parental report. After the second immunization, 100% of preterm infants had evidence of specific antibody production against diphtheria, tetanus, and pertussis. The incidence of side effects was low, but irritability was significantly more common in preterm infants after the second immunization. These observations suggest that the initiation of primary immunization with DTP in preterm infants need not be delayed beyond 2 months of age.

Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age.

To evaluate the safety and immunogenicity of the Haemophilus influenzae type b polysaccharide vaccine, PRP, and a new polysaccharide-diphtheria toxoid conjugate vaccine, PRP-D, a collaborative study was carried out in six centers in five states. Subjects were 585 infants 15 to 24 months of age. They were randomly assigned to receive a single dose of PRP or PRP-D vaccine. There were no significant differences in the rate of adverse reactions between the two vaccine groups. Minor local reactions occurred in 10.3% of PRP and 12.5% of PRP-D recipients, and fever in 27.4% of PRP and 23.8% of PRP-D recipients. All reactions resolved within 48 hours. Serum samples were obtained just before vaccination and after 1 month. Prevaccination antibody levels were similar for the PRP (0.035 micrograms/mL) and PRP-D (0.027 micrograms/mL) groups, with no differences in levels by age, sex, race, vaccine lot, or study site. Both groups had significant rises in geometric mean levels, but this difference was significantly greater for PRP-D (2.166 micrograms/mL) than for PRP (0.154 micrograms/mL). In addition, the percentage of responders as determined by three definitions (twofold titer rise, greater than 0.15 micrograms/mL, and greater than 1.0 micrograms/mL) was also significantly greater for PRP-D than PRP. In contrast to a marked age-related immunogenicity to PRP (P less than 0.001), there was no significant variation in immune response to PRP-D by age. PRP-D conjugate vaccine appears to be as safe and significantly more immunogenic than PRP vaccine for children vaccinated at 15 to 24 months of age.

DTP reactions and serologic response with a reduced dose schedule

In a double-blind study, infants received standard (0.5 ml) or modified (0.25 ml) doses of DTP vaccine for the primary series of three immunizations administered at 2, 4, and 6 months of age and the booster immunization at 18 months. Side effects and antibody responses were determined in 80 children who completed the primary series and 73 who received the booster. The modified regimen was associated with significantly reduced febrile reactions and behavioral changes after the primary series and booster inoculation: 63.2% of those who received the standard dose had febrile reactions, compared to 42.3% who received the modified dose during the primary series; a similar difference was observed with the booster. Only 47.2% of the reduced dosage recipients demonstrated marked behavioral changes, and 62.4% of the standard vaccine recipients had comparable reactions. An even larger difference (33.3% vs 64.7%) was noted at the time of the booster. The modified vaccine produced a local reaction incidence of 58.5%, compared to 72.6% in the control population during the primary immunization series; no differences were noted in local reactions with the booster dose. All patients had serologic evidence of protective titers against diphtheria and tetanus. After the primary immunization series, 97.6% and 97.3% of the infants given the modified and standard doses, respectively, had pertussis agglutinin titers of greater than or equal to 1:16. One patient who received the standard dosage had a titer of less than 1:16 one month after the booster immunization, whereas all those given the modified dose had titers greater than or equal to 1:16. Geometric mean titers of pertussis agglutinins were higher in the standard vaccine recipients after the primary series, but were similar in the two study groups before and after the 18-month immunization.

Pediatric diphtheria and tetanus toxoids-adsorbed vaccine: immune response to the first booster following the diphtheria and tetanus toxoids vaccine primary series.

Diphtheria and tetanus toxoids (DT) vaccine should be given to children at 2, 4 and 6 months of age when there are contraindications to the administration of pertussis vaccine. We have previously reported that such children develop protective antitoxin antibody levels to diphtheria and tetanus antigens. This follow-up study evaluates the decay in antitoxin antibody levels and the booster response elicited to DT antigen when a fourth dose is given at approximately 18 months of age. Twenty-three children receiving DT vaccine were compared to 38 receiving diphtheria and tetanus toxoids-pertussis (DTP) vaccine. The prebooster antibody titer to diphtheria and tetanus at approximately 18 months of age had declined below the recommended protective level in one child who had received DT vaccine and in three children who had received DTP. Following the 18-month booster dose of DT and DTP vaccine, all of the children had protective titers to diphtheria and tetanus toxin. These results suggest that the adjuvant effects of pertussis vaccine are not required to achieve adequate immunization to diphtheria and tetanus when currently available DT vaccine is used in early childhood.

Primary immunization with diphtheria-tetanus toxoids vaccine and diphtheria-tetanus toxoids-pertussis vaccine adsorbed: comparison of schedules.

In a double blind study patients were randomly divided into two groups. All patients received an initial immunization with diphtheria-tetanus toxoids-pertussis (DTP) vaccine at 2 months of age. One population received diphtheria-tetanus toxoids (DT pediatric) vaccine at the time of the second immunization at 4 months of age and DTP vaccine at 6 months (DTP-DT-DTP). In a second group DTP vaccine was administered as the second immunization and DT (pediatric) vaccine was given at the 6-month visit (DTP-DTP-DT). There was a significantly increased incidence and severity of adverse reactions associated with DTP vaccine when contrasted with responses observed after DT vaccine; differences were apparent whether the vaccine was administered as the second or the third immunization. All patients had serologic evidence of protection to diphtheria and tetanus following completion of either primary series. The geometric mean titer of pertussis agglutinins was similar in the two study groups 2 months after the second DTP immunization but was significantly higher in the DTP-DT-DTP group at 1 to 2 months after the completion of the primary immunization series (P less than 0.01). Both groups, however, were significantly lower than the comparable geometric mean titer measured after a series of three DTP inoculations (7.51, log2) (P less than 0.01). This study supports the recommendation that three immunizations of DTP be administered in the first year of life.

512 HEMOPHILUS INFLUENZAE TYPE B(HIB) POLYSACCHARIDE VACCINE: SAFETY AND IMMUNOGENICITY OF PRP AND PRP-D CONJUGATE VACCINES IN CHILDREN 16|[ndash]|24 MONTHS

A multicenter study of the relative safety and immunogenicity of the purified heat-sized Hib polysaccharide (PRP) and conjugate (PRP-D) vaccines was conducted in 475 children 16-24 months of age. No serious reactions occurred in either group. Except for fewer febrile reactions in the PRP-D group (p<.05), other reactions were similar for both vaccines.Immune responses were measured by KIA (ug)ml and are summarized below:Although PRP is soon to be licensed for use in older children, PRP-D is at least as safe and significantly more immunogenic.

1134 STUDIES OF SAFETY AND IMMUNOGENICITY OF HAEMOPHILUS INFLUENZAE TYPE B POLYSACCHARIDE DIPHTHERIA TOXOID CONJUGATE VACCINE (PRP-D) IN CHILDREN 7–14 MONTHS OF AGE

In a multicenter study, 502 normal infants ages 7-14 months were randomized to receive either 2 doses of PRP-D intramuscularly containing 20 ug PRP (80%) or placebo (20%) 6-10 weeks apart. Serum samples were obtained from 25% prior to each injection and 1 month post second dose and tested by Farr-type radioimmunoassay for anti-PRP antibody. Reaction data are available from 400 subjects. The incidence of local erythema at the injection site was 2.4% and irritability 3% in both groups. Two PRP-D recipients had temperatures greater than 1022(R). Among 120 children tested for antibody, 99% of PRP-D recipients demonstrated a two fold or greater rise in anti-PRP compared with 5% of placebo recipients. Median anti-PRP levels in the two groups were 7.0 and 0.012 ug/ml respectively. After 2 doses of PRP-D, 95% had ≥ 0.15 ug/ml antibody protein/ml and 90% had > 1 ug/ml. This study confirms prior observations in 9-14 month olds that PRP-D can induce primary and booster antibody responses in infants over 7 months compatible with protection against H. influenzae b disease.

RESPONSE TO A BOOSTER DOSE OF H.influenzae TYPE B CAPSULAR POLYSACCHARIDE - DIPHTERIA TOXOID CONJUGATE VACCINE (PRP-D) IN CHILDREN INITIALLY IMMUNIZED AT 3- 5-7 OR ONLY 7 MONTHS

22 three months old children received three doses of PRP-D at 2 months intervals, and 21 only one dose when 7 months old. In both groups half of the children received booster immunization at 14 months, and the other half at 18 months. Sera were obtained prior and post immunizations and anti-PRP antibody levels were measured by Farr-type RIA. The vaccine was well tolerated; only mild reactions were noted. The antibody responses to initial immunization have already been published (Lancet, 1985): The third dose at 7 months resulted in high antibody levels, whereas only one dose at 7 months did not. The geometric mean (GM) antibody levels before booster immunization at 14 months were 1.02 ug/ml in children who had received 3 doses of PRP-D and 0.22 ug/ml when only 1 dose had been given.The post booster levels (GM) were 40.41, 43.56, 25.41 and 37.21 ug/ml in the four groups. All groups differed significantly from any group of children of the same age immunized with PRP only (GM levels below 1 ug/ml).In conclusion. A PRP-D booster given at 14 or 18 months to children who were previously immunized at 3-5-7 or only 7 months was well tolerated and resulted in significantly higher antibody levels than immunization by PRP alone does. This suggests that PRP-D can induce a real booster effect.

HALF DOSE DPT VACCINE INADEQUATE FOR PRETERM INFANTS

The Am. Acad. of Peds. currently recommends primary immunization in preterm infants with full dose FD (0.5ml) DPT vaccine at at 2, 4 & 6 mos. after birth. Pediatricians, in an attempt to lessen side effects in preterm infants, often administer this vaccine in reduced dosage. No data exist to support this practice. This study was designed to quantitate the immune response of preterm infants immunized with half dose HD (0.25ml) vaccine and to determine the nature and extent of side effects. 10 study infants (mean ± SD BW 1.4±.3 kg, GA 31 ±2 weeks) were immunized with HD vaccine IM at 2, 4, & 6 mos. after birth. 22 preterm infants of similar BW & GA immunized with FD vaccine at the same time intervals served as controls. Prior to each immunization & 2 mos. after the 3rd, DPT specific antibodies were quantitated. Side effects were determined by parental report. The table demonstrates the % of preterm infants receiving HD & (in parenthesis those receiving FD) who had D & T protective antibodies, and % conversion for P at each time interval.D & T antibody titers were protective after DPT #2 in both groups, but the immune response to P antigen was inadequate in the HD group even after DPT#3. There were no significant differences in incidence or severity of side effects between treatment groups. Therefore, we strongly recommend that preterm infants receive full dose vaccine at the routine time intervals to insure adequate protection.