Lance K. Gordon

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.

Safety and immunogenicity of haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age†

Sixty 9- to 15-month-old infants were randomly assigned to receive two doses, 1 month apart, of a Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) or PRP vaccine, each containing 20 micrograms PRP. There were no significant local or systemic reactions. After one dose of PRP-D, 93% of the subjects attained levels of greater than or equal to 0.15 microgram/ml and 59% achieved greater than or equal to 1 microgram/ml antibody protein. These percentages rose to 100% and 86%, respectively, after the second dose, at which time the geometric mean titer of anti-PRP antibody was 4.8 micrograms/ml. IgG anti-PRP levels were 4.3 times higher than IgM. The proportion of IgG to IgM antibody induced by PRP-D increased with age. After two doses, 33% of the PRP recipients responded with a level of greater than or equal to 0.15 microgram/ml and only 19% responded to a level of greater than or equal to 1.0 microgram/ml. One year later, all of the PRP-D recipients tested still had greater than or equal to 0.15 microgram/ml and more than half had greater than or equal to 1.0 microgram/ml antibody protein.

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.

Simultaneous administration of Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine with routine diphtheria-tetanus-pertussis and inactivated poliovirus vaccinations of childhood.

A Haemophilus influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) is capable of protecting infants against invasive H. influenzae diseases. Therefore it is very likely that it will be incorporated in routine vaccination schedules during the next few years. In order to test the suitability of simultaneous administration of PRP-D and other vaccines we administered it to 25 infants mixed with diphtheria-tetanus-pertussis vaccine at 3, 4 and 6 months and simultaneously, but in a separate syringe, with inactivated polio vaccine at 12 months. A comparison group of equal size received only diphtheria-tetanus-pertussis and inactivated poliovirus vaccines. The concentration of postvaccination antibodies to diphtheria toxoid was 0.411 IU/ml in the group that received PRP-D vs. 0.352 IU/ml in the comparison group, to tetanus toxoid 3.666 vs. 3.668 IU/ml and the neutralization titer to poliovirus type 1 was 370 vs. 320 units in the comparison group, to type 2 titer values were 230 vs. 270 units and to type 3, respectively, 210 vs. 290 units. Thus the seroresponse to antigens in routine vaccines was not affected by the presence of PRP-D in the vaccination schedule, and PRP-D can safely and effectively be included in the vaccination schedule of infancy.

Persistence of antibody and response to booster dose of Haemophilus influenzae type b polysaccharide diphtheria toxoid conjugate vaccine in infants immunized at 9 to 15 months of age

At approximately 2 years of age, 27 infants previously immunized at 9 to 15 months of age with two doses of polyribosylribitol phosphate-diphtheria toxoid conjugate vaccine (PRP-D) and 23 infants immunized with polyribosylribitol phosphate (PRP) vaccine were given a single injection of PRP-D. Pre- and post-immunization sera were obtained. No serious local or systemic reactions were observed. The PRP-D recipients had a geometric mean anti-PRP antibody level of 4.8 micrograms/ml 1 month after the second primary injection, retained 1.2 microgram/ml 1 year later, and had a level of 71 micrograms/ml after the booster immunization. In contrast, PRP recipients had a geometric mean level of 0.083 microgram/ml 1 month after the second primary injection, retained 0.042 microgram/ml 1 year later, and after a single dose of PRP-D at approximately 2 years of age had a geometric mean level of 8.6 micrograms/ml. The significantly higher antibody response in the prior PRP-D recipients suggests the recall of immunologic memory induced by the PRP-D vaccine.

PERSISTENCE OF ANTIBODY (AB) TO HAEMOPHILUS INFLUENZAE TYPE B (HIB) AND RESPONSE TO PRP AND PRP-D BOOS-TER IMMUNIZATION IN CHILDREN INITIALLY IMMUNIZED WITH EITHER VACCINE AT 15 TO 24 MONTHS

Children initially imnunized with PRP or PRP-D conjugate vaccines between 15 and 24 months of age were assessed 1 year later for persistence of AB and response to revaccination with PRP, PRP-D, or normal saline (N=111). Pre and post-vaccination sera were obtained and anti-PRP antibodies were assayed by RIA. Adverse reactions were minor and noted in <5% of vaccinees. AB levels a year after initial immunization were significantly higher in subjects immunized with PRP-D(GM 1.12 ug/ml) than with PRP (0.22 ug/ml)(p<.0001). All groups demonstrated an increase in anti-PRP levels after revaccination, although this response was significantly greater in subjects initially immunized with PRP-D, regardless of booster vaccine given. Initial vaccine:Children immunized with PRP or PRP-D between 15 to 24 months of age respond dramatically to reimmnunization one year later, although children previously immunized with PRP-D show the greatest responses even with conventional PRP antigen.

1184 SERUM ANTIBODY (Ab) KINETICS FOLLOWING H. INFLUENZAE TYPE B POLYRIBOSEPHOSPHATE (PRP)-DIPHTHERIA TOXOID CONJUGATE (PRP-D) VACCINE GIVEN TO INFANTS: 1 YR FOLLOW-UP AND BOOSTER DOSE RESPONSE

We have previously reported a 90% (28/31) anti-PRP Ab response following administration of 3 doses of PRP-D to 3 mo. old infants. The resulting group geometric mean (GM) Ab cone was 0.99 μg/ml (1.4 μg/ml in responders). Sera has been obtained from 25 subjects at 6 mos., and 8 subjects at 12 mos. postvaccine. As expected, anti-PRP cone had dropped in 24/25 at the 6 mo. followup, but was still ≥0.15 μg/ml in 60% (12/20) of those who had previously achieved a titer of ≥0.15 yg one month after dose 3. The 6 mos. GM Ab conc for these 25 subjects decreased from 0.883 μg/ml to 0.163 μg/ml (p<0.01). At 12 mos. post-vaccination, 5/7 children had a further drop (one 6 mos. sera not obtained), but 62% (5/8) had an anti-PRP conc. ≥0.15 μg/ml (group GMT - 0.163 μg/ml). All 8 subjects received a 4th dose of PRP-D at 18 mos. of age (12 month follow-up) without adverse reactions. Excellent anti-PRP responses have developed in the 3 subjects studied to date, a 23 to 137-fold increase over their previous peak Ab cone (2.7 μg/ml, 5.6 μg/ml and 31.3 μg/ml).In summary, anti-PRP Ab cone ≥0.15 μg/ml was present in 60% of subjects vaccinated at age 3 mos. when evaluated at 6 and 12 mos. postvaccine. A 4th booster dose at 18 mos. did not result in any adverse reaction and induced excellent anti-PRP responses. The remaining subjects are being revaccinated and Ab evaluated.

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.

1135 RESPONSE TO A BOOSTER DOSE OF H. INFLUENZAE TYPE B CAPSULAR POLYSACCHARIDE-DIPHTHERIA TOXOID CONJUGATE VACCINE (PRP-D) IN CHILDREN INITIALLY IMMUNIZED AT 9–14 MONTHS

Thirty 9-14 month olds received 2 doses of PRP and 30 PRP-D intramuscularly 1 month apart in mid-1983, and were given a single dose (booster) of PRP-D 1 year later. Reactions were monitored for 24-48 hours. Sera were obtained prior to each immunization, 1 month post second dose and booster and tested for anti-PRP antibody by Farr or SPRIA techniques. Only mild local reactions, mainly erythema, were noted post booster in 25% of both groups. No febrile or systemic reactions were reported. 1 month post second dose, PRP recipients had a mean anti-PRP concentration of 0.08 ug/ml which fell to 0.04 ug after 1 year. The percent with 1 ug/ml anti-PRP fell from 22% at 1 month post second dose to 9% at 1 year. Among PRP-D recipients, mean levels of anti-PRP fell from 4.8 ug/ml at 1 month post second dose to 1.2 ug at 1 year. 86% had anti-PRP of ≥ 1 ug/ml 1 month post second dose compared with 59% at 1 year, but none had less than 0.15 ug/ml. 1 month following a booster dose of PRP-D, geometric mean anti-PRP concentrations were 8.6 and 71.1 ug/ml (p=0.001) for prior PRP and PRP-D recipients respectively, 90% of the prior PRP recipients reached 1 ug/ml compared with 100% of the prior PRP-D group. Prior PRP and PRP-D recipients responded equally with IgM as well as IgG antibodies.IN CONCLUSION: A PRP-D booster at 2 years of age to children who previously received 2 doses of PRP-D or PRP 1 year previously was well tolerated and resulted in a high level of antibody.