PRP-D Vaccine Research Articles

Extended follow-up of antibody levels and antigen responsiveness after 2 Haemophilus influenzae type b conjugate vaccines

Although immunization programs with Haemophilus influenzae type b (Hib) conjugate vaccines have dramatically reduced disease incidence, few data are available regarding the duration of protection after vaccination. We measured serum anti-polyribosylribitol phosphate (PRP) levels in healthy 4- to 5- year-old children previously given 4 doses of PRP-T vaccine (at 2, 4, 6, and 18 months) or 1 dose of PRP-D vaccine (at 19 months) during clinical trials to assess antibody persistence. Concurrent with other preschool immunizations, half of the children were randomly assigned to receive a PRP-T booster immunization to assess responsiveness. Among 136 subjects who were primed with PRP-D, the baseline geometric mean concentration of antibody was 0.7 μg/mL (95% CI 0.5 to 0.9). Concentrations were <0.15 μg/mL in 24 (17.6%) subjects. Among 212 children who were primed with PRP-T, the geometric mean concentration was 2.2 μg/mL (95% CI 1.9 to 2.5) ( P < .001). Only 2 (0.9%) had concentrations <0.15 μg/mL. Four weeks after PRP-T immunization, geometric mean concentrations had increased to 98.4 and 102.0 μg/mL, respectively. Responses were strong even in those with low or undetectable preimmunization antibody levels. Spontaneous increases in antibody levels were seen in 9 (5.2%) of 172 subjects not given additional PRP-T. We concluded that among 4- to 5-year-olds, anti-PRP levels remained above 0.15 μg/mL in nearly all children after PRP-T priming and in most after PRP-D priming, and that both groups were able to respond vigorously to restimulation, consistent with persistent immune memory. (J Pediatr 1999;135:240-5)

Haemophilus influenzae type b-specific antibody in infants after maternal immunization.

To study the kinetics of Haemophilus influenzae type b (Hib)-specific antibody in infants born to mothers immunized with an Hib polysaccharide or one of two Hib conjugate vaccines. Serum antibody to the polyribosylribitol (PRP) moiety of Hib was measured by radioimmunoassay and enzyme-linked immunosorbent assay at birth and at 2 and 6 months of age in infants born to women immunized with Hib polysaccharide or conjugate vaccine (PRP-D and HbOC). A subset of infants > or = 6 months of age was immunized with Hib conjugate vaccine after licensure of this vaccine for infants. A comparison group of 18 infants born to unimmunized women received the same Hib conjugate vaccine on a similar schedule. Total PRP antibody concentrations were 1.50, 14.4 and 20.4 microg/ml in 2-month-old infants born to mothers immunized with polysaccharide, PRP-D and HbOC vaccines, respectively, and 2.54, 1.35 and 2.46 microg/ml in 6-month-old infants. Infants born to mothers immunized with polysaccharide vaccine had significantly less PRP antibody at 2 months of age but similar antibody concentrations at 6 months of age. Persistence or increases in total PRP antibody during 6 months were noted in 21 of 47 (44.6%) study infants. A subset of study and comparison infants was immunized with a mean of 2.6 doses of Hib vaccines between 6 months and 2 years of age, and all infants had total PRP antibody concentrations > or = 0.15 microg/ml. Conjugate Hib vaccines administered during the last trimester of pregnancy resulted in significantly higher PRP antibody titers in infants at birth and 2 months of age than did polysaccharide vaccine. A subset of infants born to immunized mothers was subsequently immunized with Hib conjugate vaccine and had antibody concentrations similar to those in infants born to nonimmunized women.

Haemophilus influenzae b-vaccination: the urgency for timely vaccination.

In Germany the annual number of systemic Haemophilus influenzae cases in unvaccinated children aged 3-60 months has recently been exceeded by the number of cases in children vaccinated at least once with the PRP-D, HbOC or OMP vaccines, which until 1995 have almost exclusively been used for H. influenzae b (Hib) vaccination. Most of the vaccinated children however could already have had more vaccinations at onset of disease. How much does an age-related suboptimal vaccination status increase the risk for systemic H. influenzae infections? A case control study was performed in West Germany. Cases with systemic H. influenzae infections were ascertained between 7/92 and 8/ 94 with an ongoing active hospital surveillance programme. Six age-matched population controls per case were recruited at random. Only vaccinated cases and controls were included in the study. The main exposure analysed in this study was suboptimal vaccination at censoring; for censoring ages (age at disease onset in cases and corresponding age in matched controls) > 6 months: one vaccination in 1st year only; > 18 months: two (three for combined vaccines with Hib + DT or DPT in one syringe) vaccinations in the 1st year of life but no booster vaccination. Suboptimal vaccination for age increased the risk for systemic H. influenzae infections by a factor of 4.74 (95%-CI 2.17-10.34). Following adjustment for confounders the odds ratio was 4.39 (95%-CI 1.74-11.07). Subgroup analyses showed that this risk was not related to the type of vaccine used. The risk for "no booster vaccination" in children aged > 18 months appeared even greater than the risk associated with one vaccination in the 1st year only. On schedule and complete Hib vaccinations are essential for an optimal effectiveness of Hib vaccination programmes. Booster vaccinations between 12 and 18 months are important if the PRP-D, HbOC and OMP vaccines are used for primary vaccination.

Clinical Comparison of the Haemophilus influenzae Type B Polysaccharide-Diphtheria Toxoid and the Oligosaccharide–CRM197 Protein Vaccines in Infancy

To compare two Haemophilus influenzae type B (HiB) conjugate vaccines, a polysaccharide-diphtheria toxoid conjugate (PRP-D) vaccine and an oligosaccharide-CRM197 protein conjugate (HBOC [PRP-CRM]) vaccine, in the same population. One hundred twenty-five thousand infants were randomized to receive the PRP-D or HBOC vaccine. Primary immunization consisted of two doses of either vaccine administered at 4 and 6 months and a booster dose was given at 14 to 18 months. Protection was assessed by recording episodes of invasive disease with HiB isolated from the blood or another normally sterile body site. One thousand thirty-six child health care centers in Finland. Infants born in Finland during the 24-month period from 1987 to 1989. Each vaccine dose was injected intramuscularly in a volume of 0.5 mL. At the same time, a separate site was injected with the diphtheria and tetanus toxoids and pertussis vaccine at 4 months of age, with inactivated poliovirus vaccine at 6 months of age, and with measles-mumps-rubella vaccine at 14 to 18 months of age. The mean anticapsular antibody concentration 1 month after the second dose was 0.63 micrograms/mL and 4.32 micrograms/mL in the PRP-D and HBOC vaccine recipients, respectively. The booster dose resulted in a high antibody concentration: 33.3 micrograms/mL and 58.3 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. At 36 months of age, the antibody concentration declined to 2.5 micrograms/mL and 5.6 micrograms/mL for PRP-D and HBOC vaccine recipients, respectively. After two doses of the vaccine, there were five episodes (39 were expected based on historical controls) of invasive HiB disease in the PRP-D group and two episodes (35 were expected) in the HBOC group. Hence, an 87% (95% confidence limit [CL], 69, 96) protection rate in the PRP-D group and a 95% (95% CL, 76, 99) protection rate in the HBOC group were achieved. No episodes occurred after the booster dose in either group. Both the PRP-D and HBOC vaccines are safe and effective. A two-dose primary vaccination schedule seems appropriate, at least in circumstances prevailing in Finland and probably in other areas with similar epidemiological effects of HiB disease.

Finnish Efficacy Trials with Haemophilus influenzae Type b Vaccines

The first Finnish trial with Haemophilus influenzae type b vaccine was conducted during 1973-1974. It demonstrated that the polysaccharide vaccine was 90% efficacious in children greater than or equal to 18-24 months old. The immunologically superior polysaccharide-protein conjugate vaccines have been used since 1986 in randomized trials. The PRP-D vaccine (polysaccharide conjugated to diphtheria toxoid) was 90% efficacious when given at 3, 4, and 6 months of age to 58,000 infants. In 1988-1989, the PRP-D vaccine was compared with the HbOC vaccine (oligosaccharide conjugated to CRM197 protein). Follow-up is continuing, but both vaccines seem to be efficacious after two doses in infancy.

Limited Efficacy of aHaemophilus influenzaeType b Conjugate Vaccine in Alaska Native Infants

The prevention of invasive Haemophilus influenzae type b disease requires a vaccine that is effective when administered during the first six months of life. The infants of Alaska Natives are at particularly high risk of invasive H. influenzae type b disease. To evaluate the protective efficacy of a H. influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]), we enrolled 2102 Alaska Native infants in a randomized, double-blind, placebo-controlled trial in which either the vaccine or a saline placebo was administered at approximately two, four, and six months of age. After 3969 subject-years of follow-up and 32 episodes of H. influenzae type b disease, the overall incidence of invasive disease was not reduced significantly in the vaccinated subjects (6.0 cases per 1000 patient-years), as compared with the placebo controls (9.6) or with other Alaska Native infants (6.0). After one, two, or three doses there was no significant protective efficacy with the vaccine; after three doses the efficacy was only 35 percent (95 percent confidence interval, -57 to 73). The lack of efficacy was not related to the age at onset of disease, age at immunization, type of disease, degree of Alaska Native heritage, time after immunization, or year of the study. Levels of H. influenzae type b anticapsular antibody in recipients of the vaccine became significantly higher than levels in those who received placebo only after the second and third doses. Even after the third dose, only 48 percent of the vaccinated infants had antibody levels of more than 0.1 microgram per milliliter (geometric mean titer, 0.18). Antibody responses did not vary with the level of maternally acquired antibody, degree of Alaska Native ancestry, or age at time of the first or second immunizations, but they increased with increasing age at time of the third dose (P less than 0.001). We found no evidence that the PRP-D vaccine provides significant protection, at least for Alaska Native infants, against invasive diseases caused by H. influenzae type b. The ineffectiveness of the vaccine paralleled its limited immunogenicity.

Haemophilus influenzae Type b Conjugate Vaccines: Immunization of Children at 15 Months of Age

This statement updates previous information and recommendations regarding Haemophilus influenzae type b conjugate vaccines. The four vaccines that have received extensive clinical investigation and/or licensure by the United States Food and Drug Administration (FDA) are listed in the Table. Previously, the Committee recommended that all infants be immunized at 18 months of age with one of the two conjugate vaccines, designated PRP-D and HbOC, that were licensed at that time.1, 2 A third conjugate vaccine, designated PRP-OMP and consisting of the capsular polysaccharide of H influenzae type b complexed with outer membrane proteins of Neisseria meningitidis, was licensed by the FDA in December 1989. Currently, the FDA has approved labeling for PRP-OMP, HbOC, and PRP-D vaccines that states "Administration of Haemophilus b Conjugate Vaccine may be considered for children as young as 15 months of age when it is expected that the child will not return at 18 months for Haemophilus b immunization." After review of the data available on immunogenicity for PRP-D, HbOC, and PRP-OMP administered to children at 15 months of age, the Committee concludes that all children should be immunized at 15 months of age. BACKGROUND Before the introduction of immunization against H influenzae type b, it was estimated that annually approximately 16 000 cases of invasive infection occurred in the United States in children 5 years of age or younger.3 About 26.6% of cases occurred in children 18 months of age or older, and approximately an additional 9.3% occurred in children 15 to 17 months of age.

Haemophilus influenzae Type b Conjugate Vaccine (Meningicoccal Protein Conjugate): Immunogenicity and Safety at Various Doses

The Haemophilus influenzae vaccine consisting of purifled type b capsular polysaccharide (polyribosylribitolphosphate [PRP]) was shown in Finland to be protective, with 90% efficacy in children older than 18 to 23 months of age.1 However, a wide range of estimates of vaccine efficacy has been reported in the United States after its licensure in 1985.2,3 These estimates range from –55%2 to +89%.3 In addition, the PRP vaccine was not effective in children younger than 18 months of age, in whom 70% to 80% of meningitis cases occur. A further development was the introduction of H influenzae type b polysaccharide-protein conjugate vaccines such as the PRP-D. These conjugate vaccines were found to be more immunogenic than PRP vaccine in children of all ages.4,5 Two doses of PRP-D in infants 7 months of age and older induced antibody levels equal to or greater than levels in infants 24 months of age who received the PRP vaccine alone. Recently, Eskola et al6 reported that repeat vaccinations with PRP-D at 3, 4, 6, and 14 months of age was 83% protective (95% confidence interval, 26% to 96%). Yet PRP-D vaccine elicits only low serum antibody levels in infants younger than 7 months of age. Because of the discrepancy in efficacy results for the PRP vaccine in the United States and Finland and the lack of data about the protective efficacy of PRP-D vaccine in infants in the United States, the PRP-D vaccine is currently recommended only for children 18 months of age or older.7 Clearly, a vaccine that is more immunogenic in the younger population is needed.

Commentary: Results of Efficacy Trials in Alaska and Finland of Haemophilus influenzae Type b Conjugate Vaccine

One of the currently licensed Haemophilus influenzae type b polysaccharide conjugate vaccines currently recommended for use in children 18 months of age and older, polyribosylribitol-phosphate-diphtheria toxoid (PRP-D, Connaught Laboratories), has been evaluated in two studies for its protective efficacy in children immunized before 6 months of age.1 The peak incidence of invasive disease caused by H. influenzae type b occurs in children 6 to 18 months of age; therefore, prevention of this disease depends on the efficacy of vaccines in this younger age group. In a large, randomized, unblinded trial conducted in Finland, relatively low levels of antibody were induced after a series of three primary PRP-D immunizations at 3, 4, and 6 months of age. Despite these limited immunogenicity results, a high level of protective efficacy was shown during a 3-year period (protective efficacy of 87%, 95% confidence intervals 50% to 96%). Another trial, which was randomized, double blind, and placebo controlled, was conducted among 2113 Native Alaskan infants immunized (20 µg/0.5 mL) at 2, 4, and 6 months of age as part of their routine childhood immunizations. This population was chosen for the trial because it has the highest known incidence of invasive disease caused by H influenzae type b, and a trial in such a high-risk population could be conducted more carefully, with fewer study subjects, and in a shorter period of time. As in the Finnish trial, in this younger age group immune responses to PRP-D vaccine were meager, apparent only after the third dose of vaccine at 6 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.

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.

ANTIBODY RESPONSE TO HEMOPHILUS INFLUENZAE, TYPE B (HITS) PRP-D CONJUGATE VACCINE IN IMMUNOCOMPROMISED (IC) PATIENTS &lt;2 YEARS OF AGE

IC children <2 yrs represent a group at increased risk of invasive HITB infection. PRP-D conjugate vaccine (Connaught) was administered IM to 9 IC children aged 2-23 mo to assess their antibody response. Three had solid tumors (1 hepatoblastoma, 1 Wilm's, 1 neuroblastoma), 3 had sickle cell disease, 1 had AML, 1 had ALL and 1 was on immunosuppressive therapy post hepatic transplant. All cancer patients were in remission. There were no serious side effects following vaccine administration, and no children have had documented HITB infection to date. Pre and 1 mo post vaccine HITB antibody levels were measured by RIA; mean pre vaccine level was 0.025 μg/ml (range <0.012-0.12), and mean post vaccine level was O.460 μg/ml (range <0.012-1.89). Only 2/9. children achieved a protective titer ( >1 μg/ml). Of the non-responders, 4/7 were >18 mo. Three children, 16-21 mo, received a 2nd vaccine dose 1 mo after the first, and 1 responded. These data provide preliminary information regarding the response of IC children <2 yrs to PRP-D conjugate vaccine and indicate that IC children 18-23 mo do not reliably respond to a single dose of vaccine.

RESPONSE OF IgG SUBCLASS DEFICIENT PATIENTS TO H. INFLUENZA TYPE b POLYRIBOSE PHOSPHATE (PRP) DIPHTHERIA TOXOID CONJUGATE (PRP-D) VACCINE

The efficacy of PRP-D vaccine in young infants has been documented in previous studies. We now report the response of patients with IgG subclass deficiency (GSD) to a single immunization with PRP-D. Patients with GSD ranging in age from 6 to 10 years were given a single i.m. dose of 20 μg PRP-D. Total serum anti-PRP antibody levels were determined using a modified Farr assay and radiolabeled PRP. Four patients with GSD and no major abnormalities in B- and T-cell subsets or in vitro mitogen stimulation had a mean preimmunization anti-PRP level of 1.61 μg/ml which rose to 22.6 μg/ml 3-4 weeks after immunization. The mean increase in anti-PRP for 3 patients with IgG2 deficiency was 18.8 μg/ml. Two patients with IgA and IgG2 deficiency responded with post-immunization anti-PRP levels of 10.8 and 40 μg/ml. Both of these patients failed to respond to immunization with a polyvalent pneumococcal polysaccharide (PS) vaccine. One patient with isolated IgG3 deficiency responded normally to diphtheria and tetanus toxoid, to 3 of 4 pneumococcal serotypes tested, and had a rise of anti-PRP antibody from 0.6 to 28.4 μg/ml. A fifth patient with common variable immunodeficiency had no response to immunization with any of the above vaccines. These data suggest that protein conjugate vaccines may lead to effective immunization of patients with defective PS antigen processing.

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.

Serum opsonic activity after immunization of adults with Haemophilus influenzae type b-diphtheria toxoid conjugate vaccine

We measured the uptake of radiolabeled Haemophilus influenzae type b by human polymorphonuclear leukocytes. Haemophilus influenzae type b strains were preopsonized in individual sera from six adults immunized with type b polysaccharide vaccine (PRP) or six adults immunized with PRP covalently coupled to diphtheria toxoid (PRP-D vaccine). Serum was heat inactivated before use, and exogenous human complement was added. Of the 12 subjects, 3 had high levels of opsonic activity (greater than 40% of immune control) in their preimmunization serum. This activity did not correlate with the concentrations of anti-PRP antibody and was unaffected by absorption of anti-PRP antibody. At 1 month after vaccination, the serum of PRP-D subjects had higher opsonic activity than that from subjects who received PRP (5% serum, mean PRP-D = 86%, mean PRP = 53%, P = 0.001). After 12 months, both groups had higher serum opsonic activity than before immunization (P less than 0.02), but there was no difference between the two groups (mean PRP-D = 48%, mean PRP = 51%). In postimmunization serum, opsonic activity induced by PRP-D or PRP vaccines correlated directly with anti-PRP antibody concentrations as measured by a radioantigen binding assay. We conclude that both vaccines induce opsonic activity, opsonic activity induced by immunization of adults correlates well with the concentration of anti-PRP antibody achieved, and in preimmune sera with low concentrations of anti-PRP antibody, factors other than anti-PRP antibody contribute to opsonic activity.

Immunogenicity of Haemophilus influenzae type b polysaccharide—diphtheria toxoid conjugate vaccine in adults

The capsular polysaccharide of Haemophilus influenzae type b is a poor immunogen in human infants. In an attempt to enhance immunogenicity, this polysaccharide was covalently coupled to diphtheria toxoid and the conjugate tested as a vaccine in adult volunteers. Two injections of PRP-D vaccine were given, separated by one month. The anti-PRP antibody responses in this group were compared with those in a group receiving a comparable dose (20 micrograms) of conventional PRP vaccine. Both vaccines were well tolerated. A single injection of PRP-D was significantly more immunogenic than PRP, eliciting higher serum concentrations of total anti-PRP antibody 1 month later (geo means of 248 and 62 micrograms/ml, respectively; P less than 0.001). In addition, higher concentrations of IgG anti-PRP antibody were observed in the PRP-D group (P less than 0.001). One month after reinjection of vaccine, subjects receiving PRP-D showed a small but significant decline in total antibody (P = 0.03), whereas the serum antibody concentrations in the group that received PRP remained unchanged. At 12 months, the antibody concentrations of the two groups were not significantly different. Bactericidal activity and passive protection activity (infant rat model) were tested in pooled sera from the three highest and three lowest responders in each vaccine group; both PRP and PRP-D vaccines induced biologically active anti-PRP antibody. Thus PRP-D was found to elicit biologically active serum antibody and to be more immunogenic in adults than PRP vaccine; however, the duration of higher concentrations of antibody was transient.