Safety, tolerability and immunogenicity of low dose Haemophilus Influenzae type B conjugated to the outer membrane protein complex of Neisseria Meningitidis group B

Infants vaccinated with three doses followed by a booster of either 1.0 μg of Haemophilus influenzae type b conjugated to the outer membrane protein complex of Neisseria meningitidis group B or H. influenzae 10-μg oligosaccharide vaccine conjugated to 25 μg mutant toxin (CRM197) isolated from Corynebacterium diphtheriae had protective anti-polyribosylribitol phosphate concentrations. Until the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines, Hib was the most common cause of invasive bacterial disease among children in North America. 1 Vaccination has led to substantial declines in disease incidence in the United States and Canada. 1–3 Hib conjugate vaccine use has been largely limited to the world’s more developed countries. Worldwide only an estimated 2% of Hib disease is prevented by vaccination. 4 A 7.5-μg dose of Haemophilus influenzae type b conjugated to the outer membrane protein complex of Neisseria meningitidis group B (PRP-OMPC) in a liquid formulation was licensed in 1996 based on safety and immunogenicity comparable with the original 15-μg lyophilized formulation. 5 The high antibody responses observed after one dose of either the 15-μg or 7.5-μg dosage of PRP-OMPC vaccine and data suggesting that pneumococcal polysaccharides conjugated to the same carrier protein, at concentrations as low as 1 μg/dose, were immunogenic after multiple doses 6 prompted the present study. The purpose of the present study was to compare the safety, tolerability and immunogenicity of three doses of 1 μg PRP-OMPC, in an investigational liquid formulation, given at 2-month intervals followed by a booster dose at age 14 months, to licensed HbOC vaccine given at the same intervals. Methods. The study was an open label pilot study and was approved by the Saint Louis University Institutional Review Board. Written informed consent was obtained from parents before enrollment of their infants. From July, 1994, to May, 1996, healthy 2-month-old infants were recruited from participating pediatric practices in St. Louis, MO, and were randomized (2:1) to receive either the 1.0-μg liquid preparation of PRP-OMPC (Merck & Co., Inc., West Point, PA) or H. influenzae 10-μg oligosaccharide vaccine conjugated to 25 μg mutant toxin (CRM197) isolated from Corynebacterium diphtheriae (HbOC; HibTITER, Wyeth-Lederle Laboratories, Pearl River, NY). Subjects were enrolled at a number of subsites, but subject numbers were used across the subsites in strict ascending order. Subjects were given three doses of Hib vaccine, 2 months apart, followed by a booster dose at 14 months of age. Whole cell DTP and oral polio vaccines at 2, 4 and 6 months of age and hepatitis B vaccine at 2 and 6 months of age, the vaccines then recommended in infancy, were administered concurrently. Serum samples (5 ml) were collected before the second and third injections, 1 month after the third injection, before the booster dose and 1 month after the booster dose. Serum samples were assayed for antibody to H. influenzae capsular polysaccharide by radioimmunoassay at Merck Research Laboratories. Body temperature and signs of local and systemic reactions were recorded 6, 24, 48 and 72 h after vaccination on Vaccination Report Cards. Geometric mean antibody concentrations (GMCs) and 95% confidence intervals were calculated. Between group comparisons were made by analysis of variance. Serologic data were transformed to logarithms before analysis. Exact 95% confidence intervals were calculated for response rates. SAS software (SAS, Inc., Cary, NC) was used for statistical calculations. Results. Seventy-five infants received three injections of vaccine (50 in the PRP-OMPC group and 25 in the HbOC group); 74 of the 75 infants received a booster injection. The investigational 1-μg PRP-OMPC vaccine was generally well-tolerated. No serious vaccine-related adverse experiences were reported. The most common adverse experiences in both treatment groups were pain, redness and swelling at the injection site, all of which resolved within 72 h. There were no statistically significant differences in adverse experience rates between treatment groups. Compared with infants in the HbOC group, infants in the PRP-OMPC group had higher anti-polyribosylribitol phosphate (PRP) antibody concentrations after Doses 1 and 2 (P < 0.0001) (Table 1). Seventy percent of infants in the PRP-OMPC group had an anti-PRP concentration of >0.15 μg/ml after Dose 1 compared with 8.3% in the HbOC group. After the third dose of vaccine 74.0% of infants in the PRP-OMPC group and 84.0% in the HbOC group achieved anti-PRP concentrations of >1 μg/ml. After the booster dose 92.0 and 100% in the PRP-OMPC and HbOC groups, respectively, had anti-PRP antibody concentrations >1 μg/ml. Postbooster anti-PRP concentrations in the HbOC group were higher than those in the PRP-OMPC group (37.29 μg/ml vs. 10.90 μg/ml, P = 0.0015).Table 1: GMCs and percent of subjects with anti-PRP concentration > 0.15 μg/ml and > 1.0 μg/ml summarized by vaccine dose and treatment groupDiscussion. The postbooster GMC increases observed in this study support the conclusion that infants were immunologically primed after receipt of a three dose series of either the investigational PRP-OMPC vaccine or HbOC vaccine. Concentrations of anti-PRP of ≥0.15 μg/ml for short term and ≥1.0 μg/ml for long term protection generally have been accepted as surrogates of protection against Hib disease. 7, 8 Thus young infants in this study developed protective anti-PRP concentrations after either vaccine. Prevaccination anti-PRP concentrations were not measured. The anti-PRP concentrations produced after three primary series doses and a booster of the 1-μg investigational PRP-OMPC vaccine were generally comparable with those seen in clinical trials of two primary series doses and a booster of both the lyophilized 15-μg and liquid 7.5-μg dosages. 9 The concurrently administered childhood vaccines used in this study were those recommended for routine use at the time the study was conducted. Although in the present study there was a statistically significant difference in antibody concentration between the two groups of infants after the booster dose, the clinical relevance of this finding is not known. Subsequent to this study a clinical trial compared a 1-μg dose of PRP-OMPC with licensed HbOC in >300 South African infants vaccinated at 6, 10 and 14 weeks of age, followed by a booster dose at 9 months of age; preliminary data from this study are similar to those presented here. 10 Studies in the Dominican Republic of fractional doses of Hib polysaccharide-tetanus toxoid conjugate vaccine (PRP-T) and in Chile of PRP-T and HbOC have found that the fractional doses studied were comparable in immunogenicity with those of standard dosing regimens of these vaccines. 11, 12 Among the licensed Hib conjugate vaccines, PRP-OMPC is unique in that in previous studies it has demonstrated the highest first dose response. 13–16 In this trial the investigational dose of PRP-OMPC stimulated an antibody response higher than that of HbOC after the first dose. In the current conjugate vaccine era in the US, the peak incidence of invasive Hib disease has shifted downward to 5 months of age. 17 Furthermore in many developing countries where vaccine uptake is limited, very young infants have the highest burden of Hib disease. 4 The cost of Hib conjugate vaccines has limited their use primarily to industrialized countries. 11, 12 The availability of lower dosage Hib conjugate vaccine has the potential to improve Hib vaccine uptake in developing countries and thus to help reduce the global Hib disease burden. Acknowledgment. This study was supported by a grant from Merck & Co., Inc.

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