The development of the Haemophilus influenzae type b (Hib) vaccines was stimulated by the recognition that Hib was a major pathogen of early childhood and that the greatest impact on disease would only be through its prevention. One of the important early observations was the description of the inverse relationship between age and bactericidal ability of serum.1 The recognition that this in turn reflected serum antibody to the capsular polysaccharide of the organism, polyribosylribitol phosphate (PRP), and that this antibody was capable of providing protection against invasive disease led to the development of the first generation vaccine consisting of purified PRP. This proved to be a successful vaccine in older children but failed to protect those <2 years of age, the age group with the highest burden of disease.2 The conjugation of PRP to protein was the vital leap in technology that resulted in Hib vaccines potentially capable of protecting infants.
Demonstration of immunogenicity and the ability to induce immunologic memory made it likely that Hib conjugate vaccines would protect infants against invasive Hib disease, but efficacy trials were needed to establish this clearly. Each of the licensed conjugate vaccines has been subject to prospective controlled trials, and these are reviewed here. In general these trials were performed with different study designs, vaccine schedules and populations, which limits any conclusions about relative efficacies. Furthermore the effectiveness of these vaccines is best judged by their impact on the incidence of Hib disease once they are introduced into a population, and experience from several countries that have used conjugate vaccines is described.
Finland, 1985. The first field trial of a Hib conjugate vaccine took place in Finland beginning in 1985.3, 4 All infants born between October 1, 1985, and September 30, 1986, were eligible to enroll. If born on an odd-numbered day, vaccination with PRP-diphtheria toxoid conjugate (PRP-D) was scheduled for the ages of 3, 4, 6 and 14 to 18 months, and if born on an even-numbered day, it was scheduled at 24 months of age. This latter group therefore served as controls. The other routine vaccines of diphtheria-pertussis-tetanus (DPT) at 3, 4 and 5 months; inactivated poliovirus at 6 and 12 months; and measles-mumps-rubella vaccine at 14 to 18 months were administered simultaneously but by separate injections.
It was estimated that 98% of eligible infants participated in this trial, with ∼30 000 in each study group. Fourteen cases of invasive Hib disease were recorded up to February 28, 1987: 12 in the control group; and 2 in the PRP-D vaccine group. The point estimate of efficacy of three doses, therefore, was 83% [95% confidence interval (95% CI), 26 to 96%]. The average follow-up at this point was 5 months after the third dose of vaccine.3
Further analysis was performed after ∼114 000 children were enrolled in the study (born October 1, 1985, to August 31, 1987), with 58 000 in the vaccine group (median ages of vaccination, 3.1, 4.2, 6.4 and 17.3 months) and 56 000 infants in the control group; follow-up was now to the age of 24 months.4 Sixty-eight cases occurred in fully vaccinated children; 4 had received three doses of PRP-D, vs. 37 in the comparable control group (vaccine efficacy, 90%; 95% CI, 70 to 96%). No cases were detected in infants who had received 4 doses of PRP-D, as compared with 27 in the control group. The overall protective efficacy for the period 7 to 24 months of age, and including the intervals before and after the booster dose of PRP-D, was calculated to be 94% (95% CI, 83 to 98%). Among partially vaccinated children there were 4 cases in PRP-D recipients (3 after 1 dose, 1 after 2 doses) and 8 in the control group (vaccine efficacy, 50%; P = 0.25; Table 1).
Alaska. Alaskan native children have a high level of Hib disease, which peaks in early infancy, so they were an obvious group for whom to provide Hib vaccines. From the point of view of an efficacy trial (with an effective vaccine), relatively small sample sizes were likely to be sufficient. Subjects were recruited for this trial between October, 1984, and January, 1988, and randomly assigned to receive PRP-D or a saline placebo.5 Immunizations were scheduled at 2, 4 and 6 months of age, and other routine immunizations were given at separate injection sites. The infants were resident in six of the eight most populous Alaskan Native Health Board Service Units, and thus 79% of all Alaskan native births potentially could have been included in the trial.
During the 45-month period to June, 1988, 5982 Alaskan natives were born in the 6 study areas. Vaccine was administered to 1054 infants and placebo to 1048; the remainder were not recruited to the study. The median ages of vaccine doses were 1.7, 4.2 and 6.7 months. Thirty-two episodes of invasive Hib disease occurred among the study population and 42 in the nonstudy population. After 3 doses of vaccine 7 cases (excluding a recurrent episode) occurred among PRP-D vaccinees and 12 among placebo recipients (efficacy, 43%; 95% CI, −43 to 78%); if the recurrent case is included (Table 1) then efficacy was 35% (95% CI, −57 to 73%). There was no trend to protective efficacy after 1 or 2 doses of PRP-D.
Finland, 1988. After the result of high protective efficacy with PRP-D was obtained, it was not possible, for ethical reasons, to continue trials in Finland with an unvaccinated control group. Therefore a study was launched in which PRP-D was compared with PRP oligosaccharides conjugated to mutant diphtheria toxin CRM197 (HbOC),6 and efficacy calculations were based on historical data.7
Vaccination commenced on January 2, 1988, and was offered to all infants born in Finland. In contrast to the first trial primary immunization consisted only of two doses, at 4 and 6 months of age, with a booster dose at 14 to 18 months of age. DPT vaccine was administered at a separate site at 3, 4 and 5 months of age; inactivated poliovirus at 6 and 12 months of age; and measles-mumps-rubella vaccine at 14 to 18 months of age. PRP-D was given to those born on odd-numbered days and HbOC was given to those born on even-numbered days.
Of the 125 129 children born in the country during the 24-month study period, at least 117 000 (93.5%) were estimated to have received a Hib vaccine. The estimated number of vaccinees was 60 500 for PRP-D. During follow-up to September 1, 1991, 11 cases of Hib disease occurred among recipients of PRP-D. After 2 doses of PRP-D there were 5 cases, and another 5 cases occurred after 1 dose of PRP-D (excluding 1 case 6 days after receipt of vaccine). No cases were seen after the booster dose of vaccine (with follow-up to 24 months of age). These observed numbers were compared with those expected from the prevaccine era to arrive at the following estimates of efficacy: 87% (95% CI, 69 to 96%) after 2 doses (excluding vaccinees with early postvaccination disease) and 47% (95% CI, −52 to 85%) after 1 dose. Protection after the booster dose was 100% (95% CI, 88 to 100%; Table 1).
Finland, 1988. HbOC was compared with PRP-D in a national study in Finland with enrollment between 1988 and 1990 (see above). An estimated 56 500 infants received HbOC; during follow-up until September 1, 1994, only 2 cases were seen after 2 doses of vaccine (given at 4 and 6 months of age) and 1 after 1 dose. No cases were seen after the booster dose at 14 to 18 months of age (with follow-up to 24 months of age). Based on historical rates of disease, the estimated vaccine efficacy was 89% (95% CI, 26 to 100%) after 1 dose, 95% (95% CI, 79 to 99%) after 2 doses and 100% (95% CI, 87 to 100%) after the booster dose (Table 2). The difference in efficacy between PRP-D and HbOC was not statistically significant.
US: Northern California. A controlled clinical trial with HbOC was undertaken in study centers within the Northern California Kaiser Permanente Medical Care Program.8 It began in February, 1988, initially involving 7 centers and then expanding to 16 in September, 1988. HbOC was offered at 2, 4 and 6 months of age and was given concurrently with DPT and oral polio vaccines (OPV). Initially those born on the first 5 days of the month were not offered HbOC, and this interval was increased to 6 days in May, 1989, and 7 days in June, 1990, to build sufficient numbers for the unvaccinated control group (which also included those who refused Hib vaccine).
By June 30, 1990, 20 800 infants had received 3 doses of HbOC (58.4% of children in the group offered HbOC actually received vaccine) and 18 862 in the control group had not received any Hib vaccine. The mean age at the third dose was 7.2 months, with 84% having received the third dose by 8 months of age. By 18 months of age (mean duration of follow-up, 7.5 months), there had been 12 cases among the unvaccinated control group and none among recipients of 3 doses of HbOC (Table 2; efficacy, 100%; 95% CI, 68 to 100%). Because there were no cases after 2 doses of vaccine (25 481 infants; mean follow-up, 7.2 months), efficacy was also 100% (95% CI, 47 to 100%). Three cases occurred after 1 dose (30 400 infants), giving an efficacy of 26%. Two supplementary analyses that adjusted for various possible sources of bias yielded similar results.
US: Southern California. A case-control study was conducted in Los Angeles County between January, 1991, and December, 1992, to assess the protective efficacy of Hib conjugate vaccines given in infancy.9 Cases of invasive Hib disease were detected through active surveillance and were enrolled in the study if they were between 6 weeks and 35 months of age, lived in a home with a telephone and had caretakers who could speak either English or Spanish (absence of these criteria excluded only 2.5% of cases). For the purpose of efficacy calculations the number of vaccine doses was defined to include only those doses received 15 days or more before the diagnosis of Hib disease. Random digit dialing of telephone numbers in Los Angeles County was used to find controls who were matched to a case by age (±2 months) and residence. Potential confounding variables were controlled for in a multivariate analysis. One hundred nineteen cases were detected and eligible for inclusion, and full immunization history was available in 105. Twenty-seven children developed Hib disease after receiving 1 dose or more of HbOC vaccine (presumably at the recommended 2-, 4- and 6-month schedule) and the remaining 78 cases were unvaccinated. There were no cases of Hib disease after other Hib conjugate vaccines, although only 5% of the control children had actually received PRP conjugated to outer membrane protein of Neisseria meningitidis group B (PRP-OMP) and 3% PRP-D or PRP conjugated to tetanus toxoid (PRP-T). To derive estimates of vaccine efficacy, 767 controls were matched to cases. Three doses of HbOC was calculated to provide 92.5% efficacy (95% CI, 69.5% to 98.8%), 2 doses 90.1% (95% CI, 68.1% to 97.8%) and 1 dose 73.3%; 95% CI, 46.7 to 87.6%) (Table 2). Adjustment for potential confounding variables did not alter efficacy estimates significantly.
PRP-OMP (US: ARIZONA)
After the demonstration of immunogenicity of PRP conjugated to outer membrane protein of N. meningitidis group B among Navajo and Apache infants, a double blind, placebocontrolled trial was initiated.10 Navajo or Hopi infants living on the Navajo Indian Reservation (Arizona, US) were eligible to enroll and were randomized to receive either vaccine or saline placebo at ∼2 and 4 months of age. DPT and OPV were administered simultaneously but separately. The study began on July 1, 1988, and its end points included reaching the age of 18 months, receipt of a booster dose of vaccine or invasive Hib disease.
The trial was stopped on August 1, 1990, by the independent monitoring committee after 23 cases of Hib infection had occurred. During the 25-month period 5190 infants were enrolled with approximately one half receiving PRP-OMP (2588, 2056 of whom had 2 doses) and the other half placebo (2602; 2105 had 2 doses). The mean age at the first dose of vaccine was 1.8 months, with a mean of 2.3 months between the first and second doses and a mean of 8 months of follow-up after the second dose. When all subjects were included in the analysis of efficacy at 18 months of age, 1 case was found among the vaccine group and 22 among the placebo group (estimated vaccine efficacy, 95%; 95% CI, 72 to 99%). Including only those who received 2 doses, the efficacy was 93% (95% CI, 53 to 98%; Table 3). When this is modified to include only those cases occurring before 15 months of age, the efficacy was 100% (95% CI, 81 to 100%) after at least 1 dose and 100% (95% CI, 67 to 100%) after 2 doses. No cases occurred between receipt of the first and second doses (100%; 95% CI, 41 to 100%).
UK. The first controlled intervention study with PRP-T vaccine to be completed began on May 1, 1991, with recruitment until October, 1992, at which time national immunization was commenced.11 It took place in the Oxford Health Region, in which there were 8 districts and a total population of about 2 500 000. Vaccine was offered in only 4 of the 8 districts until October, 1992; the other 4 districts therefore served as the control group. PRP-T was offered at the accelerated schedule of 2, 3 and 4 months of age with DPT and OPV given simultaneously but at separate sites. Measlesmumps-rubella vaccine was administered at 13 to 15 months of age.
The mean ages of vaccination were 2.4, 3.8 and 5.0 months, and it was estimated that by October, 1992, 27 860 infants had received at least one dose (consent rate, >90%). By October 1, 1992, no vaccinees had developed invasive Hib disease, whereas 11 cases were recorded in unvaccinated control children (efficacy, 100%; 95% CI, 80 to 100%). Analysis of efficacy was done again at January 1, 1993, because <2% of control infants had by then received Hib vaccine as part of the national program. One case of Hib disease had occurred in a vaccinee and 18 cases among control children (efficacy, 95%; 95% CI, 74 to 100%; Table 3). A case-control analysis also was done, yielding similar estimates. By November, 1993, no further cases had occurred among vaccinees (average age of follow-up, 22 months).
US: Northern California. Another efficacy study with PRP-T was begun in August 1989 among infants in 13 selected clinics of the Southern California Kaiser Permanente Health Plan.12 Unfortunately the trial was terminated prematurely in October, 1990, because of the licensure and recommended routine use of HbOC for all US infants. The study was designed as a randomized, controlled and blinded study in which infants were given either PRP-T or hepatitis B vaccine at 2, 4 and 6 months of age, with DPT and polio vaccines given at separate sites.
Between August 28, 1989, and October 12, 1990, a total of 10 317 children were enrolled in the study (57% of the eligible cohort) with doses administered at about 2.2, 4.6 and 6.9 months of age. Three cases of disease occurred among the 5106 hepatitis B vaccinees and none among the 5211 PRP-T vaccinees. Although these numbers are too few to allow statistical analysis, this experience is consistent with that of the Oxford study and suggests protection against invasive Hib disease.
Another randomized, double blind, controlled study with PRP-T was conducted in North Carolina during the same period.13 Two cases of invasive Hib disease were recorded, both in recipients of the placebo vaccine.
Subsequently PRP-T has been assessed in a controlled community intervention trial in Chile and a double blind placebo-controlled trial in The Gambia. These also have yielded high estimates of protective efficacy and are described in detail elsewhere in this supplement.
All of the prelicensure clinical studies showed the conjugate vaccines to be highly protective against invasive Hib disease with one notable exception, that of PRP-D in the Alaskan native infants. Analysis of ethnic and racial background, age of first dose and interval between doses in this study revealed no effect of any of these factors on immunogenicity or efficacy; nor did the antibody concentrations achieved differ greatly from those seen in the successful Finnish study. The lot of vaccine used also did not appear to be the explanation. This emphasizes that assumptions cannot necessarily be made about the performance of a vaccine in one population based on its performance in another. In fact there probably is a fairly straightforward explanation for the Alaskan result. The most outstanding difference between this population and that of Finland was the degree of exposure to Hib. Immunogenicity studies clearly show that PRP-D is the least immunogenic of the Hib conjugates; but in a population with the epidemiologic conditions of Finland, PRP-D is more than adequate for disease control. However, in a population with a high burden of Hib disease, the lesser immunogenicity of PRP-D is likely to result in lower efficacy. In such a population a vaccine capable of inducing high levels of protective antibody at an early age is required (e.g. PRP-OMP).
The study designs used in each of the clinical trials is worth considering. The trials of PRP-D and PRP-OMP in native populations were classic double blind placebo-controlled studies, with relatively small numbers needed because of the high rates of Hib disease. Studies in populations with relatively low rates of background disease were forced to take different approaches. In Finland the entire birth cohort of the country was needed to evaluate PRP-D. Having shown this vaccine to be highly effective, the investigators were not able to maintain an unvaccinated group, but they took the opportunity to evaluate another vaccine, HbOC, in parallel. This meant that any estimates of efficacy were based on historical data, and because Hib conjugates already had been in use in the population, a reduction in carriage may have contributed to the protection of infants. In the first US HbOC study, the method chosen to accrue patients into the respective groups relatively quickly was to adjust the size of the unvaccinated control group as the trial went on. This then required the performance of extensive supplementary analyses to exclude the possibility of bias, also necessary because the proportion refusing vaccination was relatively high. Again, the vaccination of children >18 months of age also had been in place for several years, with potential beneficial effects on carriage in younger infants. A case-control study of HbOC also was possible in a US population because of the relatively low rates of vaccine coverage (20 to 60% in Los Angeles County). The infrequent use of vaccines other than HbOC at this time precluded accurate efficacy estimates for other vaccines.
In the UK the approach taken was an opportunistic one before the vaccines PRP-T and HbOC were to be introduced nationally. A placebo-controlled trial would have been unethical. Hib vaccination in one-half of the districts of one region allowed comparisons to be made with disease in the unvaccinated districts. This approach required assumptions to be made about the equivalence of disease in different areas and also used historical controls. Indeed only if double blind, randomized, with a placebo control group and inclusion of all infants would such trials be free of potential biases. None of the clinical trials satisfied all these criteria. The most meaningful demonstration of the effectiveness of a vaccine is its impact on the incidence of disease when introduced into the population under routine conditions.
It is difficult to draw conclusions about the relative efficacies of the four conjugates or of the appropriate schedules for vaccination. In fact the only trial in which two were compared side by side showed no statistically significant difference between PRP-D and HbOC.6 In a population with relatively low rates of disease the choice of vaccine probably is not critical. Furthermore a later peak age of disease will allow the use of a schedule with doses given later in the first year of life and including only two doses. Three vaccines now have been used in populations with high disease rates: PRP-D in Alaskan natives; PRP-OMP in Navajo Indians; and PRP-T in Gambian infants. Only the first of these has been found lacking. In this situation high protective efficacy has been demonstrated by PRP-OMP after just one dose given at a young age (1.8 months) and by PRP-T given in an accelerated schedule (completed by 5 months of age) and in the absence of a booster dose; either strategy might therefore be considered. It seems likely that HbOC would perform similarly well, but it has not been tested formally in this context. More interesting is the possibility of using a mixed schedule with different Hib conjugates to optimize efficacy under different conditions (e.g. PRP-OMP followed by two doses of PRP-T or HbOC); although immunogenicity studies support such an approach, there currently are no efficacy data.
EFFECTIVENESS OF WIDESPREAD IMPLEMENTATION OF HIB VACCINES
The earliest examples of the effect of vaccination on the epidemiology of Hib disease were seen in Finland and Iceland. Having vaccinated essentially the entire country as a result of the vaccine trials, Finland then witnessed a dramatic decline in disease (Fig. 1). In common with many countries that later began Hib vaccination, the observed decline was in fact more dramatic than could be expected from the numbers actually receiving vaccine. The decline of disease in unvaccinated age groups was also surprising, and these two factors suggested that the Hib conjugates were able to reduce transmission of Hib within the population. The probable explanation for this came from pharyngeal swabbing studies, which demonstrated a reduction in carriage of Hib after vaccination.15 Although other vaccines were used subsequently in Finland, PRP-D probably accounted for most of the impact on disease in this country. Disease control has been maintained subsequently with only two doses of vaccine in the first year of life and a booster dose in the second year. High vaccine coverage has been an important feature.16
The second country to use a Hib conjugate vaccine in infancy was Iceland.17 This country, with a population of 250 000 people, was able to achieve high vaccine uptake and has relied solely on PRP-D with a 3-dose primary schedule and a second year booster. It would appear that Hib disease may have been eliminated in Iceland (Fig. 2).
The US was next to introduce Hib conjugates for primary immunization of infants, and their experience is described elsewhere. Many other countries now have introduced these vaccines with impressive effects. The program in the UK is perhaps worthy of special mention. Primary immunization consists of an accelerated 2-, 3- and 4-month schedule without a booster dose of vaccine. Vaccination began in October, 1992, and a key component of the initial program was to include catch-up vaccination of all children up to 48 months of age. Vaccine coverage for both primary immunization and the catch-up component was high. Surveillance subsequently has shown a >95% reduction in disease in the 0- to 4-year-old age group and also a fall in disease rates in those age groups that have not been vaccinated (Figs. 3 and 4). In the Oxford region, where the PRP-T efficacy trial took place, continued surveillance has detected only 1 case in 1994, 1 in 1995 (both unvaccinated) and no cases in 1996. Before vaccination an annual average of 63 cases was recorded.18
Active surveillance for cases of Hib vaccine failure throughout the UK has been in place since the introduction of Hib vaccines. This has allowed estimates of efficacy to be made based on historical data (Table 4) and suggests high protective efficacy until at least the fourth year of life.19 This experience has particular relevance to developing countries, in that the schedule used is a similar one. Experience has shown that one must be careful in extrapolating data from one population to another, but the results of the Gambian and Chilean trials (described elsewhere in this supplement) suggest that PRP-T can perform with high efficacy in different countries with different burdens of Hib disease.
I thank Dr. Robert Booy for his critical reading of the manuscript.
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FIRST INTERNATIONAL CONFERENCE ON HAEMOPHILUS INFLUENZAE TYPE b INFECTION IN ASIA
The Editors thank the Association pur l'Aide à la Médicine Préventive, the Foundation Mérieux, and the World Health Organization for supporting publication of these proceedsings, and Jennifer Wells for her editorial assistance.
Keywords:© Williams & Wilkins 1998. All Rights Reserved.
Haemophilus influenzae; Haemophilus influenzae type b; vaccine; United Kingdom