Original Article
A Randomized, Prospective Field Trial of a Conjugate Vaccine in the Protection of Infants and Young Children against Invasive Haemophilus influenzae Type b Disease
N Engl J Med 1990; 323:1381-1387November 15, 1990
- Abstract
- Abstract
Background.
Haemophilus influenzae type b is the leading cause of invasive bacterial disease in young children. The capsular polysaccharide vaccine does not protect children at greatest risk (those under the age of 18 months), but a polysaccharide—protein conjugate vaccine has proved to be more immunogenic in this age group.
Methods.
We enrolled 114,000 infants in Finland in an open, prospective, randomized trial of a H. influenzae type b capsular polysaccharide—diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate—diphtheria toxoid [PRP-D]). Children born on odd-numbered days were vaccinated at the ages of 3, 4, 6, and 14 to 18 months; those born on even-numbered days formed the control group and received the same vaccine at the age of 24 months.
Results.
After three doses of the vaccine there were 4 cases of verified bacteremic H. influenzae type b disease in the group receiving early vaccination, as compared with 64 cases in the control group, between the ages of approximately 7 and 24 months. The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval, 83 to 98). No serious adverse effects were reported. The immune response to the conjugate vaccine was characteristic of a T-cell—dependent response when studied in a cohort of 120 infants. The primary immunization series resulted in a geometric mean concentration of anticapsular antibody of 0.53 μg per milliliter at the age of seven months, and the fourth dose evoked an anamnestic response, with a mean antibody concentration of 45.22 μg per milliliter.
Conclusions.
A new conjugate vaccine consisting of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier (PRP-D), administered to infants beginning at the age of 3 months, is highly effective in protecting young Finnish children (7 to 24 months old) against invasive H. influenzae type b infections. (N Engl J Med 1990; 323:1381–7.)
Media in This Article
Figure 1
Vaccination Schedule and the Follow-up Periods Used for the Calculations of Efficacy.Figure 2
Median Age of a Random Sample of 917 Children at Vaccination with PRP-D in 12 Child Health Centers.Article Activity
- Article
THE importance of Haemophilus influenzae type b bacteria as the primary cause of bacteremic infections in children has been realized only recently. In the United States, 85 percent of the approximately 20,000 cases of invasive H. influenzae type b infection occurring each year are found in children younger than 5 years of age, with a peak annual incidence of 275 per 100,000 among infants 6 to 11 months old.1
A capsular polysaccharide vaccine proved efficacious in preventing invasive H. influenzae type b disease in children who were 18 months of age or older in a prospective, randomized, double-blind trial conducted in Finland in 1974–1975.2 On the basis of these results, the polysaccharide vaccine was licensed in 1985 and recommended for general use in the United States.3 Case–control studies conducted after the vaccine was marketed, however, showed that the protective efficacy was lower than previously reported.4 5 6 7 These conflicting results suggested insufficient knowledge of the agents determining the immune response to the vaccine, epidemiologic factors, and risk factors for the disease.
The polysaccharide vaccine was at best a partial solution to the problem of preventing invasive H. influenzae type b disease. Its principal shortcoming was the inability to protect infants and children under 18 months of age. New conjugate vaccines composed of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier have different immunogenic properties than the old polysaccharide vaccine.8 They are immunogenic in young infants9 10 11 12 and induce an IgG-dominated anamnestic, or booster, response.13 The initial data on the use of a conjugate vaccine in Finnish infants14 showed a protective efficacy of 83 percent. In another efficacy trial conducted among Alaska Natives, however, a preliminary analysis showed a much lower degree of protection.15
The complete data from the prospective, randomized efficacy trial of the H. influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (composed of polyribosylribitol phosphate and diphtheria toxoid [PRP-D]) in Finland are now available. Approximately 114,000 children have been followed throughout the high-risk period of 7 to 24 months of age. We report here the final results of this study and analyze the correlation between the serologic responses and clinical protection.
Methods
Vaccines and Vaccination Schedule
The H. influenzae type b conjugate vaccine (PRP-D; bulk lots 3937, 4065, 4125, 4227, and 4601) was manufactured by Connaught Laboratories, Swiftwater, Pennsylvania. It consisted of heat-sized H. influenzae type b capsular polysaccharide (200 to 2000 kd) coupled through a six-carbon adipic acid linker to diphtheria toxoid.16 , 17 One 0.5-ml dose of PRP-D consisted of 25 μg of polyribosylribitol phosphate (PRP) and 20 μg of diphtheria toxoid administered intramuscularly in the right buttock.
The study was approved by the ethics committee of the National Public Health Institute, the National Board of Health, and all 213 local health boards. All infants born between October 1, 1985, and August 31, 1987, were eligible to participate. A public health nurse explained the study design and described the new vaccine to the parents during a visit to the child health center when the infant was approximately two months old; parents received printed information at the same time. After oral consent was obtained, children born on odd-numbered days were scheduled to receive PRP-D vaccine at 3, 4, and 6 months of age, followed by a booster dose at 14 to 18 months. The control group consisted of children born on even-numbered days; they were scheduled to receive PRP-D vaccine at 24 months of age (Fig. 1Figure 1
Vaccination Schedule and the Follow-up Periods Used for the Calculations of Efficacy.).All the children also received diphtheria–pertussis–tetanus (DPT) vaccine (manufactured by the National Public Health Institute, Helsinki) at 3, 4, 5, and 24 months of age; inactivated-poliovirus (IPV) vaccine (manufactured by the Rijksinstituut vor Volksgezondheit, Bilthoven, the Netherlands) at 6, 12, and 24 months of age; and measles—mumps—rubella vaccine (manufactured by Merck Sharp and Dohme, West Point, Pa.) at 14 to 18 months of age, according to the routine immunization schedule in Finnish child health centers (Fig. 1). Although administered simultaneously with PRP-D, these vaccines were given at a separate site (left buttock or upper arm).
Follow-up
Special arrangements were made to encourage participation, to determine the vaccination coverage (proportion of children vaccinated) and follow adverse events, and to identify bacteremic diseases in children.18 , 19 A sentinel system was established for the surveillance of enrollment that was based on regular reports from 30 randomly selected child health centers around the country. In addition, an independent sample of 12 randomly selected child health centers was visited retrospectively, and the vaccination records of the 955 children born in these centers in 1986 were examined to verify the coverage and timing of the vaccinations. Serious or unexpected adverse reactions were to be reported to the National Board of Health and the study office.
Serum samples were collected at the ages of 3, 4, 6, 7, 14, 15, and 24 months from a cohort of 120 healthy children vaccinated with PRP-D (lot 3937) at 3, 4, 6, and 14 months of age. Compliance was good: only 7 of the 120 children had dropped out by the age of 14 months. Reference values from groups of unvaccinated children were collected at the ages of 3 (n = 285), 4 (n = 197), 7 (n = 66), 14 (n = 45), and 24 (n = 297) months. Samples were also obtained on admission to the hospital and 10 to 30 days later from the few children who had H. influenzae type b disease despite vaccination. Anti—H. influenzae type b capsular polysaccharide (anti-PRP) antibodies were measured by Farr-type radioimmunoassay. The results of this assay are comparable with those from other laboratories.20 The detection limits of the assay were 0.06 and 320 μg per milliliter; concentrations below 0.06 μg per milliliter were treated as 0.06 μg per milliliter and those above 320 μg per milliliter as 320 μg per milliliter when the geometric mean concentrations were calculated. The antibody data were compared with the data from our earlier studies in which the same assay was used.9 , 12 , 13 , 21 , 22
Surveillance of bacteremic diseases in children (0 to 15 years old) was intensified in all 25 bacteriologic laboratories in the country in 1985.18 , 19 Bacterial cultures of blood, cerebrospinal fluid, or aspirates from normally sterile body sites were performed according to standard methods. In every laboratory one person (liaison) was responsible for reporting invasive H. influenzae type b infections by telephone to the study office. All bacterial strains isolated from blood, cerebrospinal fluid, or these aspirates were sent to the National Public Health Institute for confirmation of the bacteriologic identification. Furthermore, the laboratory records for the years 1985 through 1989 were reviewed retrospectively in all 25 laboratories. These data were compared with the data from the prospective survey. The relevant clinical data were collected from the records of the pediatric hospitals, and vaccination status was checked against the files of the child health centers.
Statistical Analysis
The protection against culture-verified invasive H. influenzae type b disease afforded by the vaccine was calculated as the protective efficacy23: protective efficacy = 1 − (attack rate in the vaccine group/attack rate in the control group) × 100. When calculating the vaccination coverage and the attack rates, we took into account the fact that there are 4 percent more odd-numbered days in the year than even-numbered days. The hypothesis that there was no difference between the vaccine group and the control group was tested with the statistic S = (x1 − x0)2/(X1 + x0), where x1 and x0 are the numbers of cases in the two groups after adjustment for unequal group size, with the total number of cases fixed. Under the null hypothesis S has a chi-square distribution with 1 degree of freedom.24 The 95 percent confidence interval for the protective efficacy was calculated on the basis of the ratio of the mean of two samples with a Poisson distribution. Data for children who received three doses of PRP-D (as well as three doses of DPT vaccine and one dose of IPV vaccine) in the vaccine group or the corresponding three doses of DPT vaccine and one dose of IPV vaccine in the control group were eligible for inclusion in the efficacy calculations. The follow-up for the basic immunization series consisted of the period beginning two weeks after the third PRP-D vaccination and ending after the fourth DPT and third IPV vaccinations — that is, from the age of approximately 7 months to the age of 24 months.
Results
Vaccination Coverage and Age at Vaccinations
Of 116,149 children born between October 1, 1985, and August 31, 1987, approximately 114,000 were enrolled in the study: 58,000 in the vaccine group and 56,000 in the control group. Approximately 230,000 doses of PRP-D vaccine were administered during the study. These estimates are based on data for 3252 infants born in the area served by 1 of the 30 sentinel child health centers. Of these infants, 1618 were in the PRP-D vaccine group, 1574 were in the control group, 46 children moved from the area or did not visit the child health center and could not be traced, and 14 did not take part in the study because their parents did not provide consent. The enrollment rate for this group of infants was thus 98 percent.
Independent retrospective surveys in 12 other child health centers confirmed these estimates: 468 of the 486 children born on odd-numbered days had received the full basic series of three doses of PRP-D vaccine before the age of one year, and 458 children had received the fourth dose before the age of two years. Of the 469 children born on even-numbered days, 440 were in the control group and received the control vaccine. In these centers the most common reasons not to vaccinate were parental refusal (23 cases), an inadequate number of visits to the center because of recurrent infections (15 cases), and a move out of the area (10 cases).
The median ages of the children when vaccinated with PRP-D were 3.1 months for the first dose (scheduled to be given at 3 months of age), 4.2 for the second dose (scheduled at 4 months), 6.4 for the third dose (scheduled at 6 months), and 17.3 months for the booster dose (scheduled to be given at 14 to 18 months) (Fig. 2Figure 2
Median Age of a Random Sample of 917 Children at Vaccination with PRP-D in 12 Child Health Centers.). The median age of the control group when vaccinated with PRP-D was 24.6 months (scheduled at 24 months of age).Adverse Reactions
The adverse reactions caused by the PRP-D vaccine were few and mild. The persons giving the vaccination reported 31 adverse reactions (fever, rash, irritability, and local reactions), among the 230,000 doses administered, that they considered to be clinically important and due to the PRP-D vaccination. There were no anaphylactic reactions, deaths, or permanent sequelae. One child had a hypotonic—hyporesponsive episode, and another child had convulsions after the vaccination; both had received DPT vaccine simultaneously with the PRP-D vaccine. The reactions in most cases were short-lived, and all subsided spontaneously.
Efficacy of the Vaccine
As of December 31, 1989, the intensified surveillance of invasive infections revealed 720 cases in which bacteria were isolated from the blood, cerebro-spinal fluid, or aspirates of a child born between October 1, 1985, and August 31, 1987. Ninety-one of these cases were caused by H. influenzae type b. The efficiency of the reporting system was estimated to be 97 percent: a total of 458 H. influenzae type b infections among children of any age were reported by the liaisons, as compared with a total of 471 recorded by the laboratories. Of the 13 cases of H. influenzae type b initially missed, none were in the vaccine or control group; all 91 cases in these two groups were reported by the liaisons. Of the 91 H. influenzae type b infections, 65 percent caused meningitis, 9 percent bacteremia without focus, 8 percent cellulitis, 7 percent epiglottitis, 7 percent pneumonia, and 4 percent arthritis — percentages corresponding to previous surveillance data.18 As stated earlier, all 91 infections were culture confirmed. In 83 cases the blood culture was positive for H. influenzae type b; in 54 cases H. influenzae type b was isolated from the cerebrospinal fluid (48 also had a positive blood culture); and in 4 cases the bacteria were isolated from an aspirate (2 also had a positive blood culture).
Of the 91 infections, 23 occurred in children whose data could not be used in the calculations of efficacy (Fig. 1): 8 in children who had not received even their first dose of DPT vaccine (with or without PRP-D vaccine), 12 in children in either group who had received at least one dose of DPT vaccine but had not yet received IPV vaccine (partial vaccination), and 3 in children who had already received the fourth dose of DPT vaccine. Data on vaccine efficacy were thus derived from the 68 cases that occurred in children who had received at least one dose of IPV vaccine (scheduled to be given at 6 months) but had not yet received the fourth dose of DPT vaccine, which was scheduled to be given at 24 months.
Of the 68 children with culture-verified H. influenzae type b disease, 4 had been born on an odd-numbered day and had received the full series of three doses of PRP-D vaccine but had not yet received a booster dose (Table 1Table 1
Number of Invasive H. influenzae Type b Infections among Children in the Vaccine and Control Groups up to the Age of 2 Years and the Clinical Efficacy of the PRP-D Vaccine Given at 3, 4, 6, and 14 Months of Age.). At the same time, 37 cases occurred in the relevant control group — that is, among children born on an even-numbered day who had received three doses of DPT and one dose of IPV vaccine but had not yet received measles—mumps—rubella vaccine. The protective efficacy of three doses of PRP-D vaccine in infancy was thus 90 percent (95 percent confidence interval, 70 to 96 percent). After the booster dose of PRP-D vaccine had been given there were no additional cases of invasive H. influenzae type b disease in the vaccine group, whereas there were 27 cases in the control group (Table 1). The protective efficacy of the vaccine in children between the ages of 7 months and 24 months, including the interval before and after the booster vaccination, was 94 percent (95 percent confidence interval, 83 to 98 percent).In addition to the four vaccine failures among the fully vaccinated children in the vaccine group, four cases of invasive H. influenzae type b disease occurred among partially vaccinated children, three after one dose of PRP-D and one after two doses. During the same period eight cases occurred in the control group (among those who had received one to three doses of DPT vaccine but had not yet received IPV vaccine) (Table 1).
There was no such difference between children born on odd-numbered days and those born on even-numbered days in the incidence of other bacteremic infections: 321 infections were recorded among children born on odd-numbered days (annual incidence, 170 per 100,000) and 308 infections among children born on even-numbered days (annual incidence, 169 per 100,000).
Vaccine Failures
The four children, three boys and one girl, who had invasive H. influenzae type b disease after they had received the full basic immunization series of three doses of PRP-D vaccine had previously been healthy (Table 2Table 2
Invasive H. influenzae Type b Infection among Children after the Full Basic Immunization Series.*). The blood culture from one of the boys (Patient 2) grew both Streptococcus pneumoniae (serogroup 18) and H. influenzae type b. The interval between admission and the last dose of vaccine was 55 to 173 days. The clinical picture was typical of invasive H. influenzae type b disease, and all the children recovered without sequelae. In Patients 1 and 4 a strong anti-PRP response was seen in the serum samples obtained during convalescence; equally high anti-PRP concentrations were seen in only 2 of 46 unvaccinated infants of the same age who were recovering from H. influenzae type b meningitis or sepsis.25 Serum Antibody Levels after Vaccination
The geometric mean concentration of anti-PRP antibodies was low — less than 0.1 μg per milliliter before vaccination — and remained so after the first and the second dose of PRP-D vaccine (Fig. 3Figure 3
Geometric Mean Concentration of Anti-PRP Antibodies in the Vaccine Group (Thick Line) after Immunization with PRP-D Vaccine at 3, 4, 6, and 14 Months of Age and in the Control Group of Unvaccinated Children (Thin Line).). It increased to 0.53 μg per milliliter after the third dose of PRP-D vaccine. Only 40 percent of the seven-month-old infants had an anti-PRP antibody concentration of at least 1 μg per milliliter, the previously suggested minimum for sustained protection.26 , 27 Furthermore, only 70 percent had an anti-PRP antibody concentration of 0.15 μg per milliliter or more, the minimum considered protective in unimmunized persons, and 80 percent had a concentration of at least 0.10 μg per milliliter. An antibody response (any increase in titer) was observed in 85 percent of the infants at six to seven months of age.There was little decrease in the geometric mean concentration of anti-PRP antibodies in the vaccine group between 7 and 14 months of age (from 0.53 μg per milliliter to 0.37 μg per milliliter) before the booster dose of PRP-D vaccine was given. All 113 children in whom levels were measured, including the 17 who had undetectable anti-PRP antibody levels at seven months, responded to the booster dose with an increase in the anti-PRP concentration to more than 1 μg per milliliter (Fig. 4Figure 4
Anti-PRP Antibody Response (Expressed as the Geometric Mean Concentration) to the Booster Dose of PRP-D Vaccine Given at 14 Months of Age in 113 Children.). The mean concentration at 15 months was 45.22 μg per milliliter, and it decreased to 7.98 μg per milliliter at 24 months (Fig. 3).Discussion
Three doses of PRP-D vaccine given at three, four, and six months of age were clinically efficacious in protecting against invasive H. influenzae type b disease in infancy (4 cases in children so treated, as compared with 37 cases in the control group), and the booster dose given at 14 to 18 months further increased the protection. The overall protective efficacy was 94 percent, with a narrow 95 percent confidence interval of 83 to 98 percent. These data were based on the follow-up of 114,000 children for approximately 17 months (from the age of 7 months to the age of 24 months). The large number of children and long follow-up over the period of greatest risk for invasive H. influenzae type b disease made us confident of the protective efficacy of the conjugate vaccine in infancy, at least under the epidemiologic and socioeconomic conditions in Finland.
Randomization was designed to be as easy as possible, to ensure reliability in the 1036 child health centers in which the immunizations were performed. We checked the vaccination records of 955 infants in 12 randomly selected health centers and of the children who had 720 cases of invasive infections during this study without finding a faulty group assignment.
The criteria for the diagnosis of all the invasive H. influenzae type b diseases on which the efficacy calculations were based included a positive culture from the blood, cerebrospinal fluid, or an aspirate. The disease surveillance was organized prospectively and monitored continuously; a retrospective screening of laboratory records did not reveal any additional cases. Therefore, we believe that all cases of H. influenzae type b were traced. An independent measure of the reliability of the data collection is the virtually identical annual incidence in the study groups of invasive infections caused by agents other than H. influenzae type b.
The protective immunity evoked by the conjugate vaccine seems qualitatively different from that evoked by the H. influenzae type b polysaccharide vaccine. At seven months of age, only 40 percent of the infants had serum anti-PRP antibody concentrations of at least 1 μg per milliliter and would thus have been expected to be protected if the same rules about the correlation of antibody concentration and clinical protection26 , 27 applied to the conjugate and the polysaccharide vaccines. In fact, the percentage of those protected was much higher, 90 percent. We suggest that this better-than-expected protective efficacy was due to immunologic priming demonstrated by an anamnestic response to the vaccine given at 14 months; the geometric mean concentration of antibody in the children given three doses of vaccine before this age was nearly 20-fold higher than that in children receiving their first dose of PRP-D vaccine at this age (Fig. 4). Even the infants with a very low or undetectable antibody concentration at seven months had an anamnestic response, which in all cases entailed an increase to more than 1 μg per milliliter (Fig. 4).
The Finnish experience with the polysaccharide vaccine2 differed from that in studies in the United States conducted after the vaccine was marketed.4 5 6 7 We now face the same problem in trying to compare the data from efficacy trials with the conjugate vaccines. A preliminary report from a U.S. study of 2113 vaccinated children who were mainly Alaska Native infants gave a much lower point estimate for protective efficacy.15 There are many possible reasons for this difference. The infants in our study represent a genetically homogeneous white population. The socioeconomic conditions in Finland are of a high Scandinavian standard. The mean number of children in Finnish families is relatively low, and housing conditions are rarely crowded. The Alaskan study population differed from ours in regard to all these factors.28 There were also differences in the frequency of protective factors as well as risk factors for invasive H. influenzae type b disease between these populations. Breast-feeding is common and prolonged in Finland (80 percent of the mothers breast-feed their infants for more than six months), and day care outside the home is uncommon before the age of one year.18 , 29 In addition, the antibody responses to the PRP-D vaccine were lower in Alaska30 than in Finland. Precise knowledge of both the immunogenicity of the vaccine and the risk factors in each country indeed seems essential for successful planning of national vaccination strategies. For example, a vaccination schedule aimed at protection after six months of age would be appropriate in Finland but clearly not sufficient in Alaska, where many of the infections occur at an earlier 31 , 32 age.
On the basis of our results, H. influenzae type b conjugate vaccine has been offered since January 1988 to all infants in Finland.33 At the same time the number of cases of invasive H. influenzae type b disease among children younger than five years of age has decreased, from a total of 172 in 1986 to 27 in 1989 (unpublished data). Thus, we have not only shown a statistically significant protective efficacy for the H. influenzae type b conjugate vaccine in a field trial but also demonstrated an effect on the incidence of disease.
Supported by Connaught Laboratories, Inc.
We are indebted to the liaison persons in the child health centers, pediatric wards, and microbiologic laboratories, as well as to Drs. Joel S. Samuelson and James E. Froeschle, for invaluable help; and to Hannele Lehtonen, Anu Molarius, Juni Palmgren, Panu Rekola, Leena Saarinen, Paula Solukko, and Sirkka-Liisa Wahlman for skillful technical assistance.
Source Information
From the National Public Health Institute, Helsinki, Finland (J.E., H.K., A.K.T., H.P., P.-R.R., E.K., E.P., P.H.M.), and Connaught Laboratories, Swiftwater, Pa. (P.H.McV.). Address reprint requests to Dr. Eskola at the National Public Health Institute, Mannerheimintie 166, SF-00300 Helsinki, Finland.
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