Current Trends FDA Workshop on Haemophilus b Polysaccharide Vaccine -- A Preliminary Report

In April 1985, the Food and Drug Administration (FDA) licensed the first Haemophilus b polysaccharide vaccine. Two additional companies were licensed to produce similar vaccines at the end of 1985. Estimation of the efficacy of the vaccines was based on the results of a randomized, controlled clinical trial conducted in Finland. In that trial, which was conducted among children 18-71 months of age, efficacy was estimated to be 90%, with few serious adverse reactions reported (1). In addition, each manufacturer performed safety and immunogenicity studies before licensure. Upon licensure, FDA asked each company to conduct postmarketing studies for rare adverse events in larger populations.

After licensure, FDA, CDC, the manufacturers, and individual investigators received spontaneous reports of invasive Haemophilus influenzae type b (Hib) disease in previously vaccinated children. One investigator published data suggesting that vaccine failure might be due to an inability to induce an appropriate antibody response (2). Several groups of investigators initiated studies to further evaluate the vaccine's efficacy. Investigators from Northern California Kaiser Permanente Health Plan and the Minnesota Department of Health reported observing some cases of invasive Hib disease during the 1-week period immediately following vaccination.

These observations prompted FDA to hold a workshop on April 20, 1987, to discuss the ongoing studies of the vaccine's efficacy. It was recognized that these studies were incomplete at the time of the meeting. The workshop was an open meeting involving experts in Haemophilus disease, epidemiology, and statistics. Two issues were addressed: the efficacy of the vaccine and the interpretation of reports of invasive Hib disease in the 7 days following vaccination.

Investigators from the Northern California Kaiser Permanente Health Plan, Yale University and the University of Texas, the Minnesota Department of Health, and CDC presented data. Each of these groups had been conducting studies for 2 years. Because of the normal delay in antibody formation following vaccination, the investigators had considered children to be vaccinated only if they had received vaccine 21 days or more (14 days or more in the CDC study) before the onset of disease. A brief synopsis of the data follows.

The Kaiser group presented data from a prospective cohort study and a case- control study. The former was not randomized and included about 122,000 children between 18 months and 5 years of age. There were 24 cases of invasive Hib disease in the unvaccinated group and two cases in the vaccinated group. The point estimate of the vaccine's efficacy was 89% (95% confidence interval (CI), 52 to 97). A case-control study from this cohort yielded a point estimate of 81% (95% CI, 10 to 96). Four children in this population developed disease within 7 days after vaccination. One of the patients had been immunized specifically because of exposure to Hib.

Yale University and the University of Texas conducted a joint birth-certificate- matched case-control study among children 24 to 59 months of age. Investigators identified 17 cases in Connecticut and 25 in Dallas. Twenty-four percent of the patients and 50% of the controls in Connecticut were vaccinated; in Dallas, 11% of the patients and 32% of the controls were vaccinated. The point estimate of efficacy in Connecticut and Dallas was 89% (95% CI, 69 to 97). In this study, one patient had been vaccinated within 7 days of the date of onset, and one control had been vaccinated within 7 days of the reference date, indicating no increased risk of Hib disease.

The Minnesota Department of Health conducted a birth-certificate-matched case- control study among children 24 to 59 months of age. From September 1985 to March 1987, investigators identified 53 cases. Eight of the patients were excluded because of pre-existing risks for Hib disease.* Fifteen (33%) of the 45 remaining patients were vaccinated, compared with 22 (24%) of the 90 controls. The estimated protective efficacy was -86% (95% CI, -415 to 33). The Minnesota investigators observed three cases of invasive Hib disease within 7 days of vaccination.

CDC conducted a multistate day-care-based case-control study among children 18 to 59 months of age. There were 108 patients and 251 controls. Nineteen percent of the patients and 29% of the controls had been vaccinated. The point estimate of efficacy was 44% (95% CI, -5 to 70). Investigators identified four patients with onsets of invasive Hib disease during the first week after vaccination; five controls had been vaccinated during a comparable interval.

Unlike these relatively small observational studies, the clinical trial of vaccine efficacy in Finland was a large, prospective, randomized trial involving over 48,000 recipients of Haemophilus b polysaccharide vaccine. This study is considered important because of its design and size. With the exception of the Minnesota study, all the efficacy studies presented at the April 20, 1987, workshop produced results that are not inconsistent with the results of the Finnish trial. However, since the more recent studies were observational, they may be subject to biases not usually found in randomized, controlled trials. These studies are continuing, and the data will be reassessed in the near future.

Although the Finnish study did not identify any cases of Hib disease within 7 days of vaccination, further information is necessary to evaluate the meaning of cases found soon after vaccination in the more recent studies. In any event, physicians should be aware that cases may occur in the week after vaccination, prior to onset of the protective effects of the vaccine.

While further analysis of these data is in progress, it was concluded that, based on evaluation of these preliminary data, the benefits of the vaccine continue to outweigh any potential risk. Therefore, physicians are urged to vaccinate their patients according to present ACIP recommendations.

Any adverse events, including vaccine failure, should be reported either to the manufacturer or to FDA. Reported by: Div of Bacterial Products, Div of Epidemiology and Biostatistics, Center for Drugs and Biologics, Food and Drug Administration.

References

1. Peltola H, Kayhty H, Virtanen M, Makela PH. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984;310: 1561-6.

2. Granoff DM, Shackleford PG, Suarez BK, et al. Haemophilus influenzae type b disease in children vaccinated with type b polysaccharide vaccine. N Engl J Med 1986;315:1584-90. *Including immunodeficiency, sickle cell anemia, or a previous episode of Hib disease.

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